MYH7 (3)
Case#: SF No. 29, GC Case No. 22, female, 79
DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy
FamilyInfo: No
CasePresentingHPOs: N/A
CaseHPOFreeText: Colorectal cancer,
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: WES, Sanger sequencing,
Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)
ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/
CAID: N/A
gnomAD: absent
Supplementary Data: Online Table 2a
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.2710C>T (p.Arg904Cys)
ClinVar: 164316, https://www.ncbi.nlm.nih.gov/clinvar/variation/164316/
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23893328-G-A
Supplementary Data: Online Table 1a
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3:c.2713T>C
CAID: CA389047302, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047302
gnomAD: n/a
Supplementary Data: Online Table 1a
Case:
CasePresentingHPOs: HP:0001629 (Ebstein anomaly)
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.689T>C (p.Phe230Ser)
ClinVar: 263543, https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/
gnomAD: n/a
Supplementary Data: Online Table 2a
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3:c.1208G>C
CAID: CA389051121, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051121
gnomAD: n/a
Supplementary Data: Online Table 3
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.345C>T (p.Tyr115=)
ClinVar: 42962, https://www.ncbi.nlm.nih.gov/clinvar/variation/42962/
gnomAD: 0.0001061, https://gnomad.broadinstitute.org/variant/14-23902293-G-A
Supplementary Data: Online Table 3
Case:
CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)
CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes
Variant: NM_000257.3(MYH7):c.698C>T (p.Ala233Val)
ClinVar: 177858, https://www.ncbi.nlm.nih.gov/clinvar/variation/177858/
gnomAD: n/a
Supplementary Data table 1
Variant noted to be present in 4 individuals
Variant: NM_000257.3(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T
Supplementary Data table 1
Variant noted to be present in 2 individuals
Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)
ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3:c.2306T>C
CAID: CA389048688, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048688
gnomAD: n/a
Supplementary Data table 1
Variant noted to be present in 3 individuals
Variant: NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln)
ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.1532T>C (p.Ile511Thr)
ClinVar: 42848, https://www.ncbi.nlm.nih.gov/clinvar/variation/42848/
gnomAD: n/a
Supplementary Data table 1
Case:
DiseaseAssertion: hypertrophic cardiomyopathy
CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm
CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography
CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)
Variant: NM_000257.3(MYH7):c.727C>T (p.Arg243Cys)
ClinVar: 43101, https://www.ncbi.nlm.nih.gov/clinvar/variation/43101/
gnomAD: 0.00003184, https://gnomad.broadinstitute.org/variant/14-23900799-G-A
Supplementary Material 4
Case M-21: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3:c.2302_2310del
CAID: CA913184893, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184893
gnomAD: n/a
Supplementary Material 4
Case M-12: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.1988G>A (p.Arg663His)
ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T
Supplementary Material 4
Case M-31: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.4721G>A (p.Arg1574Gln)
ClinVar: 228912, https://www.ncbi.nlm.nih.gov/clinvar/variation/228912/
gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23885445-C-T
Supplementary Material 4
Case M-11: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.1988G>A (p.Arg663His)
ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T
Supplementary Material 4
Case M-27: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2770G>A (p.Glu924Lys)
ClinVar: 14092, https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/
gnomAD: n/a
Supplementary Material 4
Case M-3: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)
ClinVar: 14088, https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/
gnomAD: n/a
Supplementary Material 4
Case M-5: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.1012G>A (p.Val338Met)
Clinvar: 164381, https://www.ncbi.nlm.nih.gov/clinvar/variation/164381/
gnomAD: n/a
Supplementary Material 4
Case M-17: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342, https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: n/a
Supplementary Material 4
Case M-13: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2011C>T (p.Arg671Cys)
ClinVar: 164350, https://www.ncbi.nlm.nih.gov/clinvar/variation/164350/
gnomAD: n/a
Supplementary Material 4
Case M-7: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)
ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: n/a
Supplementary Material 4
Case M-24: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2546T>C (p.Met849Thr)
ClinVar: 42914, https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/
gnomAD: n/a
Supplementary Material 4
Case M-4: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)
ClinVar: 14088, https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/
gnomAD: n/a
CaseMYH7-29: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 1 other proband shares this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.1988G>A (p.Arg663His)
ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: European (Non-Finnish) 3.097e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23896042-C-T
CaseMYH7-12: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 1 other proband shares this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.1358G>A (p.Arg453His)
ClinVar: 42838 https://www.ncbi.nlm.nih.gov/clinvar/variation/42838/
gnomAD: Not in gnomAD
CaseMYH7-15: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.5135G>A (p.Arg1712Gln)
ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/
gnomAD: European (Non-Finnish) 4.657e-5, Overall 2.125e-5 https://gnomad.broadinstitute.org/variant/14-23884860-C-T
CaseMYH7-10: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 3 other probands share this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2779G>A (p.Glu927Lys)
ClinVar: 42932 https://www.ncbi.nlm.nih.gov/clinvar/variation/42932/
gnomAD: Not in gnomAD
CaseMYH7-21: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 5 other probands share this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2722C>G (p.Leu908Val)
ClinVar: 14097 https://www.ncbi.nlm.nih.gov/clinvar/variation/14097/
gnomAD: European (Non-Finnish) 6.482e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23893316-G-C
CaseMYH7-8: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2539A>G (p.Lys847Glu)
ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/
gnomAD: Not in gnomAD
CaseMYH7-4: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2156G>A (p.Arg719Gln)
ClinVar: 140107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: Not in gnomAD
CaseMYH7-19: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 2 other probands share this genotype
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.4066G>A (p.Glu1356Lys)
ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/
gnomAD: Not in gnomAD
Case#: Consequence 29 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.2782G>A (p.Asp928Asn)
ClinVar: 164313 https://www.ncbi.nlm.nih.gov/clinvar/variation/164313/
CAID: n/a
gnomAD: absent
Case#: Consequence 7 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.1608G>T (p.Glu536Asp)
ClinVar: 177671 https://www.ncbi.nlm.nih.gov/clinvar/variation/177671/
CAID: n/a
gnomAD: absent
Case#: Consequence 14 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln)
ClinVar: 14087 https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/
CAID: n/a
gnomAD: absent
Case#: Consequence 16 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)
ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/
CAID: n/a
gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T
DiseaseAssertion: None
VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
Variant: NM_000257.4(MYH7):c.4399C>G (p.Leu1467Val)
ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/
gnomAD: 0.001111, http://gnomad.broadinstitute.org/variant/14-23886482-G-C
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in two HCM probands
Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His)
ClinVarID: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00003097, http://gnomad.broadinstitute.org/variant/14-23896042-C-T
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one proband
Variant: NM_000257.4(MYH7):c.1063G>A (p.Ala355Thr)
ClinVarID: 42820 https://www.ncbi.nlm.nih.gov/clinvar/variation/42820/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in two HCM probands
Variant: NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)
ClinVar: 14097 https://www.ncbi.nlm.nih.gov/clinvar/variation/14097/
gnomAD: 0.00006482, http://gnomad.broadinstitute.org/variant/14-23893316-G-C
DiseaseAssertion: None
VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
Variant: NM_000257.4(MYH7):c.3803G>A (p.Arg1268His)
ClinVar: 42975 https://www.ncbi.nlm.nih.gov/clinvar/variation/42975/
gnomAD: 0.0009786, http://gnomad.broadinstitute.org/variant/14-23888742-C-T
Supplementary Data Table S3
Case: 349
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)
ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/
gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C
MultipleGeneVariants:
(1) MYH6 Variant
Variant: NM_002471.3(MYH6):c.1763A>C (p.Asp588Ala)
ClinVar: 155811 https://www.ncbi.nlm.nih.gov/clinvar/variation/155811/
gnomAD: 0.003074, https://gnomad.broadinstitute.org/variant/14-23868065-T-G
(2) MYH6 Variant
Variant: NM_002471.3(MYH6):c.5491G>A (p.Glu1831Lys)
ClinVar: 196975 https://www.ncbi.nlm.nih.gov/clinvar/variation/196975/
gnomAD: 0.0003008, https://gnomad.broadinstitute.org/variant/14-23853725-C-T
(3) RBM20 Variant
Variant: NM_001134363.3(RBM20):c.1958C>T (p.Thr653Ile)
ClinVar: 180045 https://www.ncbi.nlm.nih.gov/clinvar/variation/180045/
gnomAD: 0.0007430, https://gnomad.broadinstitute.org/variant/10-112572113-C-T
(4) TMPO Variant
Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)
ClinVar: 44673 https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/
gnomAD: 0.005407, https://gnomad.broadinstitute.org/variant/12-98926856-G-A
Supplementary Data Table S3
Case: 179
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.3:c.2185G>C (p.Ala729Pro)
CAID: CA389048952 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048952
gnomAD: Not in gnomAD
Supplementary Data Table S3
Case: 208
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) ABCC9 Variant
Variant: NM_005691.3(ABCC9):c.2200G>A (p.Val734Ile)
ClinVar: 35627 https://www.ncbi.nlm.nih.gov/clinvar/variation/35627/
gnomAD: 0.01123, https://gnomad.broadinstitute.org/variant/12-22017410-C-T
(2) PLB1 Variant
Variant: NM_153021.4:c.275A>G (p.Lys92Arg)
ClinVar: CA1586810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_153021.5%3Ac.275A%3EG
gnomAD: 0.03209, https://gnomad.broadinstitute.org/variant/2-28748165-A-G
(3) TTN Variant
Variant: NM_001267550.2(TTN):c.33501_33503AGA[6] (p.Glu11172dup)
ClinVar: 46889 https://www.ncbi.nlm.nih.gov/clinvar/variation/46889/
gnomAD: 0.01788, https://gnomad.broadinstitute.org/variant/2-179544685-C-CTCT
Supplementary Data Table S3
Case: 18
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys)
ClinVar: 14092, https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/
gnomAD: absent
MultipleGeneVariants:
(1) LMNA Variant
Variant: NM_170707.4(LMNA):c.357C>T (p.Arg119=)
ClinVar: 48062, https://www.ncbi.nlm.nih.gov/clinvar/variation/48062/
gnomAD: 0.00424
(2) SDHA Variant
Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)
ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/
gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T
(2) TTN Variant
Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)
ClinVar: 165840, https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/
gnomAD: 0.001152, https://gnomad.broadinstitute.org/variant/2-179436256-ATTG-A
Supplementary Data Table S3
Case: 8
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants
(1) LAMA4 Variant
Variant: NM_001105206.3(LAMA4):c.2614C>G (p.Pro872Ala)
ClinVar: 180391, https://www.ncbi.nlm.nih.gov/clinvar/variation/180391/
gnomAD: 0.0004032, https://gnomad.broadinstitute.org/variant/6-112463374-G-C
Supplementary Data Table S3
Case: 110
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant1: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
Variant2: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)
ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/
gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C
MultipleGeneVariants:
(1) CRYAB Variant
Variant as listed does not exist on any transcript
Variant: c.331G>A (p.Gly111Ser)
ClinVar: N/A
gnomAD: N/A
(2) DSP Variant
Variant: NM_004415.4(DSP):c.4588G>T (p.Val1530Phe)
ClinVar: 137171 https://www.ncbi.nlm.nih.gov/clinvar/variation/137171/
gnomAD: 0.01477, https://gnomad.broadinstitute.org/variant/6-7581011-G-T
(3) SDHA Variant
Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)
ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/
gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T
(4) TMPO Variant
Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)
ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/
gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C
(5) TTN Variant
Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)
ClinVar: 165840 https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/
gnomAD: 0.003324, https://gnomad.broadinstitute.org/variant/2-179436256-ATTG-A
Supplementary Data Table S3
Case: 118
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) CSRP3 Variant
Variant: NM_003476.4:c.529G>A (p.Gly177Ser)
CAID: CA5916512 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA5916512
gnomAD: 0.00004619, https://gnomad.broadinstitute.org/variant/11-19204273-C-T
Supplementary Data Table S3
Case: 21
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) LDB3 Variant
Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)
ClinVar: 178059, https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/
gnomAD: 0.0009830, https://gnomad.broadinstitute.org/variant/10-88439888-C-T
Supplementary Data Table S3
Case: 216
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant1: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T
Variant2: NM_000257.4(MYH7):c.3853+7C>T
ClinVar: 42977 https://www.ncbi.nlm.nih.gov/clinvar/variation/42977/
gnomAD: 0.003956, https://gnomad.broadinstitute.org/variant/14-23888685-G-A
Supplementary Data Table S3
Case: 2
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) MYBPC3 Variant
Variant: NM_000256.3(MYBPC3):c.440C>T (p.Pro147Leu)
ClinVar: 181035, https://www.ncbi.nlm.nih.gov/clinvar/variation/181035/
gnomAD: 0.0005896, https://gnomad.broadinstitute.org/variant/11-47371630-G-A
(2) MYOZ2 Variant
Variant: NM_016599.4(MYOZ2):c.738A>G (p.Ile246Met)
ClinVar: 30509, https://www.ncbi.nlm.nih.gov/clinvar/variation/30509/
gnomAD: 0.002300, https://gnomad.broadinstitute.org/variant/4-120107298-A-G
(3) PSEN2 Variant
Variant: NM_000447.3(PSEN2):c.211C>T (p.Arg71Trp)
ClinVar: 192130, https://www.ncbi.nlm.nih.gov/clinvar/variation/192130/
gnomAD: 0.003711, https://gnomad.broadinstitute.org/variant/1-227071475-C-T
(4) SCN5A Variant
Variant: NM_000335.4(SCN5A):c.1715C>A (p.Ala572Asp)
ClinVar: 67683, https://www.ncbi.nlm.nih.gov/clinvar/variation/67683/
gnomAD: 0.005175, https://gnomad.broadinstitute.org/variant/3-38645378-G-T
Supplementary Data Table S3
Case: 231
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)
ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/
gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C
MultipleGeneVariants:
(1) LDB3 Variant
Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)
ClinVar: 178059 https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/
gnomAD: 0.009200, https://gnomad.broadinstitute.org/variant/10-88439888-C-T
Supplementary Data Table S3
Case: 129
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)
ClinVar: 42874 https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) LAMA4 Variant
Variant: NM_001105206.3(LAMA4):c.3239G>A (p.Arg1080Gln)
ClinVar: 44374 https://www.ncbi.nlm.nih.gov/clinvar/variation/44374/
gnomAD: 0.02400, https://gnomad.broadinstitute.org/variant/6-112460365-C-T
Supplementary Data Table S3
Case: 13
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) PLB1 Variant
Variant: NM_153021.4:c.3967C>A
CAID: CA1588921, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1588921
gnomAD: 0.01507, https://gnomad.broadinstitute.org/variant/2-28854972-C-A
(2) TTN Variant
Variant: c.33510_33512dupAGA, p.Glu11171dup Unregistered Variant
Supplementary Data Table S3
Case: 152
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) CRYAB Variant
Variant as listed does not exist on any transcript
Variant: c.331G>A (p.Gly111Ser)
ClinVar: N/A
gnomAD: N/A
(2) DSP Variant
Variant: NM_004415.4(DSP):c.4372C>G (p.Arg1458Gly)
ClinVar: 44906 https://www.ncbi.nlm.nih.gov/clinvar/variation/44906/
gnomAD: 0.003556, https://gnomad.broadinstitute.org/variant/6-7580795-C-G
Supplementary Data Table S3
Case: 138
DiseaseEntity: HCM
HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm
InheritancePattern: n/a
CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)
CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing
Variant: NM_000257.3:c.2162G>A (p.Arg721Lys)
CAID: CA389049002 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049002
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) CRYAB Variant
Variant as listed does not exist on any transcript
Variant: c.331G>A (p.Gly111Ser)
ClinVar: N/A
gnomAD: N/A
(2) SDHA Variant
Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)
ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/
gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T
(3) TCAP Variant
Variant: NM_003673.3(TCAP):c.458G>A (p.Arg153His)
ClinVar: 44710 https://www.ncbi.nlm.nih.gov/clinvar/variation/44710/
gnomAD: 0.002296, https://gnomad.broadinstitute.org/variant/17-37822316-G-A
CaseMYH7-16: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 3 other probands have the same genotype
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2681A>G (p.Glu894Gly)
ClinVar: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/
gnomAD: Not in gnomAD
CaseMYH7-40: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.937A>T (p.Ile313Phe)
CAID: CA389051713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.937A%3ET
gnomAD: Not in gnomAD
CaseMYH7-20: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2420G>A (p.Arg807His)
ClinVar: 391904 https://www.ncbi.nlm.nih.gov/clinvar/variation/391904/
gnomAD: Latino 5.644e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23894494-C-T
CaseMYH7-9: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.4066G>A (p.Glu1356Lys)
ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/
gnomAD: Not in gnomAD
CaseMYH7-23: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2225C>A (p.Ala742Glu)
ClinVar: 192310 https://www.ncbi.nlm.nih.gov/clinvar/variation/192310/
gnomAD: Not in gnomAD
WJ
CaseWJ: 30 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: One affected relative Brother (index case) died suddenly aged 34 y (MYH7 p.Asp778Val only)
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: Maximum left ventricular hypertrophy at 18 mm
CaseNotHPOs: N/A
NotHPOsFreeText: Sudden cardiac death event
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant1: NM_000257.3:c.2333A>T (p.Asp778Val)
ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/
gnomAD: Not in gnomAD
Variant2: NM_000257.3:c.5452C>T (p.Arg1818Trp)
ClinVar: 217826 https://www.ncbi.nlm.nih.gov/clinvar/variation/217826/
gnomAD: Latino 5.782e-5, Overall 7.956e-6 https://gnomad.broadinstitute.org/variant/14-23884311-G-A
CaseMYH7-33: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1727A>G (p.His576Arg)
ClinVar: 177625 https://www.ncbi.nlm.nih.gov/clinvar/variation/177625/
gnomAD: African 4.008e-5, Overall 1.768e-5 https://gnomad.broadinstitute.org/variant/14-23896955-T-C
CaseMYH7-27: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2156G>A (p.Arg719Gln)
ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: Not in gnomAD
CaseMYH7-12: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.3236G>A (p.Arg1079Gln)
ClinVar: 177826 https://www.ncbi.nlm.nih.gov/clinvar/variation/177826/
gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.073e-6 https://gnomad.broadinstitute.org/variant/14-23891398-C-T
DW
CaseDW: 16 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: One affected relative, Father, died suddenly
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: Maximum left ventricular hypertrophy at 21 mm
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.937A>T (p.Ile313Phe)
CAID: CA389051713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.937A%3ET
gnomAD: Not in gnomAD
Multiple Gene Variants:
MYBPC3 Variant
Variant: NM_000256.3:c.2372_2373insG (p.Trp792Valfs)
ClinVar: 42619 https://www.ncbi.nlm.nih.gov/clinvar/variation/42619/
gnomAD: European (Non-Finnish) 4.277e-5, Overall 1.744e-5 https://gnomad.broadinstitute.org/variant/11-47359280-A-AC
Supplementary Data: S2 Table
Case 233: Spanish, 57yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3:c.2312G>C
CAID: CA032230, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA032230
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23894602-C-G
MultipleGeneVariants:
(1) TTN Variant:
Variant: NM_133378.4:c.89954C>T
CAID: CA1986510, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.89954C%3ET
gnomAD: 0.00001430, https://gnomad.broadinstitute.org/variant/2-179406146-G-A
Supplementary Data: S2 Table
Case 156: Spanish, 82yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.5135G>A (p.Arg1712Gln)
ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/
gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T
Supplementary Data: S2 Table
Case 9: Spanish, 13yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing
Variant: NM_000257.3(MYH7):c.4124A>G (p.Tyr1375Cys)
ClinVar: 164293, https://www.ncbi.nlm.nih.gov/clinvar/variation/164293/
gnomAD: n/a
Supplementary Data: S2 Table
Case 65: Spanish, 35yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.715G>A (p.Asp239Asn)
ClinVar: 43100, https://www.ncbi.nlm.nih.gov/clinvar/variation/43100/
gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23900811-C-T
MultipleGeneVariants:
(1) MYBPC3 Variant:
Variant: NM_000256.3(MYBPC3):c.3676C>T (p.Arg1226Cys)
ClinVar: 42731, https://www.ncbi.nlm.nih.gov/clinvar/variation/42731/
gnomAD: 0.00004815, https://gnomad.broadinstitute.org/variant/11-47353761-G-A
(2) TTN Variant:
Variant: NM_001267550.2(TTN):c.49175C>A (p.Ala16392Glu)
ClinVar: 405004, https://www.ncbi.nlm.nih.gov/clinvar/variation/405004/
gnomAD: 0.000004042, https://gnomad.broadinstitute.org/variant/2-179478949-G-T
Supplementary Data: S2 Table
Case 100: Spanish, 81yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3:c.1580C>T
CAID: CA389050265, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389050265
gnomAD: n/a
Supplementary Data: S2 Table
Case 7: Spanish, 23yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing
Variant: NM_000257.3:c.2596T>C
CAID: CA389048059, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048059
gnomAD: n/a
Supplementary Data: S2 Table
Case 234: Spanish, 50yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3:c.2312G>C
CAID: CA032230, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA032230
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23894602-C-G
Supplementary Data: S2 Table
Case 251: Spanish, 55yo, Female
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.3610G>C (p.Gly1204Arg)
ClinVar: 42966, https://www.ncbi.nlm.nih.gov/clinvar/variation/42966/
gnomAD: 0.000004008, https://gnomad.broadinstitute.org/variant/14-23889170-C-G
Supplementary Data: S2 Table
Case 10: Spanish, 69yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing
Variant: NM_000257.3(MYH7):c.4377G>T (p.Lys1459Asn)
ClinVar: 43012, https://www.ncbi.nlm.nih.gov/clinvar/variation/43012/
gnomAD: 0.0002937, https://gnomad.broadinstitute.org/variant/14-23886504-C-A
Supplementary Data: S2 Table
Case 130: Spanish, 14yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2167C>G (p.Arg723Gly)
ClinVar: 42885, https://www.ncbi.nlm.nih.gov/clinvar/variation/42885/
gnomAD: n/a
MultipleGeneVariants:
(1) TCAP Variant:
Variant: NM_003673.3(TCAP):c.97C>T (p.Arg33Trp)
ClinVar: 282451, https://www.ncbi.nlm.nih.gov/clinvar/variation/282451/
gnomAD: 0.00007092, https://gnomad.broadinstitute.org/variant/17-37821709-C-T
Supplementary Data: S2 Table
Case 67: Spanish, 40yo, Male
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1
CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2389G>A (p.Ala797Thr)
ClinVar: 42901, https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894525-C-T
MultipleGeneVariants:
(1) TTN Variant:
Variant: NM_133378.4(TTN):c.4396T>C (p.Phe1466Leu)
ClinVar: 166320, https://www.ncbi.nlm.nih.gov/clinvar/variation/166320/
gnomAD: 0.0006871, https://gnomad.broadinstitute.org/variant/2-179642515-A-G
Table 1 and 4
Case A13: Male, 10yo, proband (III-2)
DiseaseAssertion: malignant HCM
FamilyInfo: positive family history (fig 1), grandfather died at 42yo from heart disease, father died at 40yo due to sudden cardiac death, mother (A11, II-1) had no clinical symptoms, sister (A12, III-1) diagnosed at 21yo with severe HCM
CasePresentingHPOs: HP:0100749, HP:0001279 (chest pain, syncope)
CaseHPOFreeText: interventricular septum thickness = 21.0mm, left ventricular posterior wall thickness = 12.0mm, left atrium = 40.0mm, left ventricular ejection fraction = 48%, septal asymmetry, decreased left ventricular systolic and diastolic function
CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)
CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing
Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)
ClinVar: 14104, https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/
gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A
MultipleGeneVariants:
(1) PRKAG2 Variant:
Variant: NM_016203.3(PRKAG2):c.298G>A (p.Gly100Ser)
ClinVar: 36697, https://www.ncbi.nlm.nih.gov/clinvar/variation/36697/
gnomAD: 0.006770, https://gnomad.broadinstitute.org/variant/7-151478406-C-T
CaseMYH7-4: Japan, Asian
CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.
Variant: NM_000257.3:c.2221G>C (p.Gly741Arg)
ClinVar: 14098 https://www.ncbi.nlm.nih.gov/clinvar/variation/14098/
gnomAD: Not in gnomAD
CaseMYH7-6: Japan, Asian
CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.
Variant: NM_000257.3:c.1511A>G (p.Glu504Gly)
CAID: CA257822944 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1511A%3EG
gnomAD: Not in gnomAD
Supplementary Data, Table 2
Case: Australian
DiseaseAssertion: HCM
CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm
CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)
CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7
Variant: NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp)
ClinVar: 14102, https://www.ncbi.nlm.nih.gov/clinvar/variation/14102/
gnomAD: n/a
Supplementary Data, Table 2
Variant noted to be present in 5 individuals
Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)
ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/
gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A
Supplementary Data, Table 2
Variant noted to be present in 3 individuals
Variant: NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342, https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: n/a
Supplementary Data, Table 2
Variant noted to be present in 2 individuals
Variant: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)
ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: n/a
Supplementary Data, Table 2
Variant noted to be present in 3 individuals
Variant: NM_000257.3(MYH7):c.1954A>G (p.Arg652Gly)
ClinVar: 177626, https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/
gnomAD: 0.000003978, https://gnomad.broadinstitute.org/variant/14-23896451-T-C
Case143: Male, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0001635, HP:0025169 (Left ventricular noncompaction, Heart failure, Left ventricular systolic dysfunction)
HPOsFreeText: Left Ventricular Ejection Fraction at 42%, LVDD-Z score at 1
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.262G>A (p.Glu88Lys)
CAID: CA389053315 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.262G%3EA
gnomAD: Not in gnomAD
Case339: Female, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635, HP:0011675 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure, Arrhythmia)
HPOsFreeText: Left Ventricular Ejection Fraction at 48%, LVDD-Z score at 1
CaseNotHPOs: N/A
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
There are two possible mutations that result in the below variant, CA389050168 and CA389050167. It is not clear which one is correct here.
Variant: NP_000248.2:p.Lys542Asn
CAID: N/A
gnomAD: N/A
Case377: Female, 0.0833 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 30%, LVDD-Z score at 1.3333
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.2078T>G (p.Leu693Arg)
CAID: CA389049168 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2078T%3EG
gnomAD: Not in gnomAD
Case391: Female, 0.83 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 38%, LVDD-Z score at 2.6785
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.5401G>A (p.Glu1801Lys)
ClinVar: 43069 https://www.ncbi.nlm.nih.gov/clinvar/variation/43069/
gnomAD: Not in gnomAD
Case362: Female, 0.0833 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)
HPOsFreeText: Left Ventricular Ejection Fraction at 40%, LVDD-Z score at -0.823
CaseNotHPOs: HP:0011675, HP:0001635 (Arrhythmia, Heart failure)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.689T>C (p.Phe230Ser)
ClinVar: 263543 https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/
gnomAD: Not in gnomAD
Phenotypes of MYH7 mutations
Variant1: NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)
ClinVar: 264607 https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/
gnomAD: 0.00001759, https://gnomad.broadinstitute.org/variant/14-23897049-C-T
Variant2: NM_000257.4(MYH7):c.2678C>T (p.Ala893Val)
ClinVar: 177763 https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/
gnomAD: Not in gnomAD
Variant3: NM_000257.3:c.2713T>C (p.Cys905Arg)
CAID: CA389047302 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.2713T%3EC
gnomAD: Not in gnomAD
Variant4: NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)
ClinVar: 264608 https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/
gnomAD: Not in gnomAD
Variant5: NM_000257.3:c.415G>T (p.Val139Leu)
CAID: CA389052864 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.415G%3ET
gnomAD: Not in gnomAD
Variant6: NM_000257.4(MYH7):c.495G>A (p.Met165Ile)
ClinVar: 524948 https://www.ncbi.nlm.nih.gov/clinvar/variation/524948/
gnomAD: Not in gnomAD
Variant7: NM_000257.3:c.547G>A (p.Gly183Arg)
CAID: CA389052574 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.547G%3EA
gnomAD: Not in gnomAD
Variant8: NM_000257.3:c.5754C>G (p.Asn1918Lys)
CAID: CA389034544 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5754C%3EG
gnomAD: Not in gnomAD
Variant9: NM_000257.3:c.5773C>G (p.Arg1925Gly)
CAID: CA257807342 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5773C%3EG
gnomAD: Not in gnomAD
Variant10: NM_000257.4(MYH7):c.689T>C (p.Phe230Ser)
ClinVar: 263543 https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/
gnomAD: Not in gnomAD
Variant11: NM_000257.3:c.715_717del (p.Asp239del)
CAID: CA913184869 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.715_717del
gnomAD: Not in gnomAD
Variant12: NM_000257.4(MYH7):c.732+1G>A
ClinVar: 14127 https://www.ncbi.nlm.nih.gov/clinvar/variation/14127/
gnomAD: 0.00005437, https://gnomad.broadinstitute.org/variant/14-23900793-C-T
Variant13: NM_000257.3:c.798T>A (p.Tyr266Ter)
CAID: CA389052023 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.798T%3EA
gnomAD: Not in gnomAD
Variant14: NM_000257.4(MYH7):c.847T>G (p.Tyr283Asp)
ClinVar: 66081 https://www.ncbi.nlm.nih.gov/clinvar/variation/66081/
gnomAD: Not in gnomAD
Variant15: NM_000257.3:c.902T>A (p.Leu301Gln)
CAID: CA389051788 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.902T%3EA
gnomAD: Not in gnomAD
CaseST4-90: Sweden
DiseaseAssertion: Idiopathic Dilated Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0002140, HP:0000822, HP:0001654, HP:0030955, HP:0000819, HP:0002666, HP:0000845, HP:0000820 (Ischemic stroke, Hypertension, Valvular heart disease, Alcoholism, Diabetes mellitus, Pheochromocytoma, Acromegaly, Thyroid disease)
NotHPOsFreeText: Patients were excluded for significant systemic infection, systemic diseases, previous cancer treatment including irradiation, and tachycardia-induced cardiomyopathy or other primary cardiomyopathy.
CaseAddInfo: N/A
CasePreviousTesting: See Supplemental Table 1
CaseGenotypingMethod: Genomic DNA was extracted from the patients. 41 exons of previously-reported genes that were reported in DCM patients were amplified and directly sequenced. Afterwards, the variants were aligned and sorted for pathogenicity.
Variant: NM_000257.3:c.2776C>G (p.Leu926Val)
CAID: CA034272 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2776C%3EG
gnomAD: South Asian 1.307e-4, Overall 1.591e-5 https://gnomad.broadinstitute.org/variant/14-23893262-G-C
CasePT-41: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.3749G>C (p.Arg1250Pro)
ClinVar: 181232 https://www.ncbi.nlm.nih.gov/clinvar/variation/181232/
gnomAD: East Asian 5.437e-5, Overall 7.958e-6 https://gnomad.broadinstitute.org/variant/14-23888796-C-G
CasePT-101: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.4353+5G>A
ClinVar: 181255 https://www.ncbi.nlm.nih.gov/clinvar/variation/181255/
gnomAD: African 1.602e-4, Overall 1.769e-5 https://gnomad.broadinstitute.org/variant/14-23886707-C-T
CasePT-111: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.563C>A (p.Thr188Asn)
CAID: CA016314 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.563C%3EA
gnomAD: Not in gnomAD
HCM041
CaseHCM041: 50 yrs report, Vietnam, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001712, HP:0100749, HP:0002875, HP:0011103, HP:0031295 (Left ventricular hypertrophy, Chest pain, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement)
HPOsFreeText: Maximal LV thickness 30 mm
CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy
CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.
Variant: NM_000257.4(MYH7):c.1324C>T (p.Arg442Cys)
ClinVar: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/
gnomAD: 0.00005012, http://gnomad.broadinstitute.org/variant/14-23898247-G-A
CaseCM1856: Male, 15 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother with an ECG abnormality and 2 brothers with HCM tested positive for this variant, Father with no phenotypes tested negative for this variant
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2155C>T (p.Arg719Trp)
ClinVar: 14104 https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/
gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A
CaseCM1829: Male, 12 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Variant is asserted as novel, Mother and father are both negative for this variant
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2459C>A (p.Ala820Asp)
CAID: CA389048368 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2459C%3EA
gnomAD: Not in gnomAD
Supplementary Data: Table S3
Case 64:
DiseaseAssertion: left ventricular noncompaction
CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)
CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1
CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.
CaseGenotypingMethod: WES, variant enrichment analysis
Variant: NM_000257.3(MYH7):c.3337-3dupC written in paper as g.23889445insG
ClinVar: 42956, https://www.ncbi.nlm.nih.gov/clinvar/variation/42956/
gnomAD: 0.02126, https://gnomad.broadinstitute.org/variant/14-23889445-T-TG
MultipleGeneVariants:
(1) - TTN Variant:
Variant: g.179407388delC no ClinVar or CAID
Supplementary Data: Table S3
Case 56:
DiseaseAssertion: left ventricular noncompaction
CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)
CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1
CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.
CaseGenotypingMethod: WES, variant enrichment analysis
Variant: NM_000257.3(MYH7):c.4717G>A (p.Glu1573Lys)
ClinVar: 222729, https://www.ncbi.nlm.nih.gov/clinvar/variation/222729/
gnomAD: 0.00005967, https://gnomad.broadinstitute.org/variant/14-23885449-C-T
MultipleGeneVariants:
(1) TMPO Variant:
Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)
ClinVar: 44673, https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/
gnomAD: 0.002714, https://gnomad.broadinstitute.org/variant/12-98926856-G-A
D15
Case#: D15, male, 43 years
DiseaseAssertion: FDCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy
CaseGenotypingMethod: N/A
Variant: NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)
ClinVar: 43005 https://www.ncbi.nlm.nih.gov/clinvar/variation/43005/
CAID: N/A
gnomAD: absent
Supplementary Table S1 & S2 Proband and Variant Information:
Case41: GT41b, Male, 13 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister is 41a in this study (See Supplemental Table S1)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000978
(Epistaxis, easy bruising)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.91del (p.Ala31Profs2) and NM_000419.3:c.2915dup (p.Leu973Alafs63)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913203486 and CA8602531
gnomAD: MAF in the East Asian population is 0.0001088 http://gnomad.broadinstitute.org/variant/17-42452054-C-CG
Supplementary Table S1 & S2 Proband and Variant Information:
Case72: GT76, Male, 54 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002239, HP:0032551
(Gi bleeding, hemorrhoids)
CaseHPOFreeText: Moderate bleeding syndrome
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Type unknown for this proband
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.2421G>A (p.Trp807Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399796017
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case8: GT9, Male, 86, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Moderate mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 10-20% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.665T>C (p.Leu222Pro) and NM_000212.2:c.1871G>A (p.Cys624Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224887 and CA400032726
gnomAD: MAF in the European (non-Finnish) population 0.00006482 http://gnomad.broadinstitute.org/variant/17-45363676-T-C
Supplementary Table S1 & S2 Proband and Variant Information:
Case42: GT42, Male, 15 years old, Egyptian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0012541, HP:0002239, HP:0031364, HP:0030137
(Cephalohematoma, GI bleeding, ecchymosis, prolonged bleeding after circumcision)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.2148dup (p.Leu717Alafs*3)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940304
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case33: GT36a, Female, 49 years old, Spanish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother who is proband 36b and affected sister who is proband 36c in this study
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225
(Epistaxis, gingival bleeding)
CaseHPOFreeText: Bleeding at the onset of menses
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case26: GT30, Female, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother (See Supplementary Table 1)
ParentalGenotype: N/A
CasePresentingHPOs:
(Epistaxis, GI bleeding)
CaseHPOFreeText: Diffuse bruising mainly with trauma
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 5-10% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.777+1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623036
gnomAD: MAF in the Latino population is 0.0006774 http://gnomad.broadinstitute.org/variant/17-45363789-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case55: GT55, Female, 28, Argentinian/Brazilian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Has an affected sister (this is all the information we are provided with)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000421
(Gingival bleeding, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 11-22% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.647C>T (p.Ala216Val)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805506
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case35: GT36c, Female, 47 years old, Spanish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister who is proband 36 a and affected brother proband 36b
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000132, HP:0011891
(Menorrhagia, post-partum hemorrhage)
CaseHPOFreeText: Intra-abdominal hemorrhage and bleeding after trauma
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case7: GT8, Male, 82 at death, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0002239
(Easy bruising, epistaxis, GI bleeding
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 10-15% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.2348+5G>C (p.Ser756Gly783delInsArg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290947484
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case47: GT47, Male, 11 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.832del (p.Asp278Ilefs*101)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940374
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case12: GT13, Female, 14, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000967 (Petechiae)
CaseHPOFreeText: Moderate bleeding syndrome
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% variant expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.682C>T (p.Gln228Ter) and NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA399805421 and CA115834
gnomAD: MAF in the East Asian population is 0.0002176 http://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Table S1:
Case2: GT3, French, age and gender not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.353T>A (p.Leu118His) and NM_000212.2:c.709_710del (p.Ser237Cysfs*13) and NM_000212.2:c.1732G>A (p.Asp578Asn)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224511 (p.Leu118His) and CA8623029 (p.Ser237Cysfs*13) and CA8623343 (p.Asp578Asn)
gnomAD: MAF in the European (non-Finnish) population in (p.Ser237Cysfs*13) is 0.00001796 https://gnomad.broadinstitute.org/variant/17-45363717-CAG-C and MAF in the Other population for (p.Asp578Asn) is 0.0008149 https://gnomad.broadinstitute.org/variant/17-45376715-G-A
Supplementary Table S1:
Case58: GT, French, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and other other variant is stated as "LR deletion" so I will note it as an Unknown Variant
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376
gnomAD: MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C
Supplementary Table S1:
Case3: GT4, French Gypsy, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A (p.Val513Leufs*71)
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
Supplementary Table S1:
Case57: GT67, French, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480SerfsTer106) and NM_000419.3:c.1618C>T (p.Gln540Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA399802411
gnomAD: MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42457504-G-A
Supplementary Table S1:
Case25: GT28, French/Syrian, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: All the supplemental table says is "LR dup" no other information is provided here (I will note this as Unregistered-please feel free to change this by commenting and letting me know)
LegacyVariant: N/A
ClinVar: N/A
CAiD: N/A
gnomAD: N/A
Supplementary Table S1:
Case19: GT22, French, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.408+11C>A and NM_000419.3:c.1259T>C (p.Va;420Ala)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940333 and CA399803733
gnomAD: N/A
Supplementary Table S1:
Case36: GT42, Canadian/Egypt, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.2148dup (p.Leu717AlafsTer3)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940304
gnomAD: N/A
Supplementary Table S1:
Case42: GT49, French/Spanish, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480SerfsTer106) and NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G for the (p.Cys705Arg) variant
Supplementary Table S1:
Case45: GT53, Argentina/Brazil, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.356G>A (p.Arg119Gln) and NM_000212.2:c.1697G>A (p.Gly566Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622925 and CA400032338
gnomAD: MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A
Supplementary Table S1:
Case24: GT27, French, gender and age were not specified here
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.2468G>A (p.Gly823Glu)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 and CA399795351
gnomAD: MAF in the European (non-Finnish) population is 0.000008791 for (p.Tyr471Ter) MAF in the African population is 0.000 for p.Gly823Glu) https://gnomad.broadinstitute.org/variant/17-42453334-C-T
Supplementary Table S1:
Case31: GT38, Sweden/USA, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.79+1G>A and NM_000212.2:c.940-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400028478 and CA400025605
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case18: Gt18, Male, 20 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1; however, very minimal information
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602626 (p.Gln891Ter)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case36: GT36, Male, 8 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0002239
(Bruising, purpura, ecchymosis, epistaxis, gastrointestinal bleeding)
CaseHPOFreeText: Intestinal intrussusception
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1913+5G>T (c.1913+5G>T)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623377
gnomAD: MAF in the East Asian population 0.0001633 https://gnomad.broadinstitute.org/variant/17-45376901-G-T
Supplementary Tables 1 and 2 combined information:
Case27: GT27, Male, 29 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1; however, very minimal information
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364
(Bruising, purpura, ecchymosis)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro) This article is not completed-Meera
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD: MAF in East Asian population: 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
Supplementary Tables 1 and 2 combined information:
Case10: GT10, Male, 8 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2236G>T (p.Glu746Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399798321
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case15a: Male, 15 years old, brother to GT15b
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1, brother to GT15b
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP, a small response to collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1525del (p.Gln509Argfs*160) and NM_000212.2:c.1199G>A (p.Cys400Tyr)
LegacyVariant: N/A
ClinVar: 13562 (p.Cys400Tyr)
CAiD: CA915940237 (p.Gln509Argfs*160) and CA123244 (p.Cys400Tyr)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case1: GT1, Female, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1051C>T (p.Arg351Ter) and NM_000419.3:c.2029G>A (p.Glu677Lys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290954030 (p.Arg351Ter) and CA399800002 (p.Glu677Lys)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case39: GT39, Male, 25 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1; however, very minimal information
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0100309 (Subdural hematoma)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 50-100% (variant) of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2570G>T (p.Cys857Phe) and NM_000419.3:c.1769G>A (p.Arg590Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399794409 (p.Cys857Phe) and CA8602943 (p.Arg590Gln)
gnomAD: MAF for (p.Arg590Gln) in the Latino population 0.0002314 https://gnomad.broadinstitute.org/variant/17-42457166-C-T
Supplementary Tables 1 and 2 combined information:
Case34: GT34, Male, 3 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421,HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.432G>A (p.Trp144Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805999
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case14: GT14, Female, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case7: GT7, Female, 31 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A (p.Arg551Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986 (p.Arg551Gln)
gnomAD: MAF in South Asian population: 0.00006536 https://gnomad.broadinstitute.org/variant/17-42457470-C-T
Supplementary Tables 1 and 2 combined information:
Case5: GT5, Female, 25 years old; however, now deceased
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132, HP:0000421, HP:0002239, HP:0002170
(Menorrhagia, epistaxis, gastrointestinal bleeding, intracranial hemorrhage)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.2159T>C (p.Leu720Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA115834 (p.Arg584Ter) and CA399798955 (p.Leu720Pro)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case2: GT2, Male, 13 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3: c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case28: GT28, Female, 6 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0002239
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, gastrointestinal bleeding)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1728del (p.S577Pfs*92) and NM_000212.2:c.892C>T (p.Gln298Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940253 (p.S577Pfs*92) and CA400025098 (p.Gln298Ter)
gnomAD: N/A
Supplemental Table S1:
Cases38and39: Females, Italy, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Moderate bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <5% αIIbβ3 expression
PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)
CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.2254C>G (p.Leu752Val) and NM_000419.3:c.2264G>C (p.Arg755Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602773 and CA8602772
gnomAD: MAF in the European non Finnish population is 0.00001032 https://gnomad.broadinstitute.org/variant/17-42454390-G-C and MAF in the European non Finnish population is 0.00001060 https://gnomad.broadinstitute.org/variant/17-42454380-C-G
PreviouslyPublished: PMID: 12083483
c.463+
PatientID: VHL 11
KindredID: VHL 11
Case: Sex, Age, Ethnicity unknown
DiseaseAssertion: hemangioblastoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: Three samples of VHL hemangioblastomas were represented here (.1, .2, .3). They are recorded as both germline and somatic, involving the VHL- and C3ORF10-gene.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A - This sample was likely duplicated in 24132471
SupplementalData: Yes - See Supplementary Table 1
Variant: c.463+3A>C
LegacyVariant: N/A
CaseProblemVariantFreeText: Supplemental data records this as a c.463+3A>C (p.(?)) mutation. The only time the text mentions a splice site mutation however is at: c.463+2T>C p.(?). Will go by supplemental data but be cautious of this discrepancy.
ClinVarID: N/A
CAID: CA645525016 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.463%2B3A%3EC
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Region (c.463+3A>C)
MultipleGeneVariants: N/A
PatientID: 224
KindredID: 83
Case: M, 53Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The patient had the same germline mutation as his sister (the proband). His sister presented with a pheochromocytoma at age 38. His mother had a CNS hemangioblastoma at 52, but no genotyping information is available for her.
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: The patient presented with renal cell carcinoma at age 53.
CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: 276
KindredID: 107
Case: M, 50Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband, patient 276, presented with a retinal angioma at age 31, and a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 37. The proband has a father who presented with a CNS hemangioblastoma at age 50.
CasePresentingHPOs: HP:0001737; HP:0001732; HP:0010797 HP:0009711 (Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Retinal capillary hemangioma)
CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at age 50.
CaseNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: Exon 2-3 Deletion (c.341-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 2-3 Deletion
MultipleGeneVariants: N/A
PatientID: 208
KindredID: 79
Case: M, 49Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband's mother and sister had a CNS hemangioblastoma at ages 40 and 50, respectively. His nephew presented with a CNS hemangioblastoma (age 15), a retinal angioma (age 27), and renal cell carcinoma (age 25). His daughter had a retinal angioma at age 14, and a CNS hemangioblastoma at age 24. No genetic testing information was available for family members.
CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0002666; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Renal cell carcinoma)
CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 29. At age 46, they presented with renal cell carcinoma and a pheochromocytoma. At age 49 they presented with multiple pancreatic cysts/tumors.
CaseNotHPOs: HP:0009711; (Retinal Capillary Hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: Kindred #79 was published in Wang et al., 2014 (PMID: 24581539). This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: 186
KindredID: 72
Case: F, 39Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.
CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001732; HP:0001737; HP:0002666 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts, Pheochromocytoma)
CaseHPOFreeText: The patient presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 37, and a pheochromocytoma at 39.
CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
M199016NoHb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule3Yesc.500G>A p.(Arg167Gln)5.75.534.6 (pheochromocytoma)
PatientID: None
KindredID: 2
Case: M, 16Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: None
CasePresentingHPOs: HP:0002666, HP:0030405, HP:0011732 (pheochromocytoma, pancreatic endocrine tumour, Abnormality of adrenal morphology)
CaseHPOFreeText: The patient had three tumours.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: Previously published in 24301059.
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 5.7%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.
MutationType: missense_variant;transition
CivicName: R167Q (c.500 G >A)
MultipleGeneVariants: N/A
WM06 VHL VHL 0.84
PatientID: WM06
KindredID: 12
Case: Sex Unknown, 10Y0M, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127
PreviouslyPublished: N/A
SupplementalData: Yes
Variant: N/A - Unspecified
LegacyVariant: Given as an unspecified germline mutation
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: N/A
CivicName: N/A
MultipleGeneVariants: N/A
VCB.14T VHL VHL 0.63
PatientID: VCB.14T
KindredID: 6
Case: Sex Unknown, 34Y0M, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma, pheochromocytoma)
CaseHPOFreeText: Presented with bilateral pheochromocytoma
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127
PreviouslyPublished: 25545346 (see table S1 and S10)
SupplementalData: Yes
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: SDHA, Germline, c.619A>C (p.Arg207=); SDHA, Germline, c.1969G>A (p.Val657Ile); KIF1B, Germline, c.2192A>G (p.Asn777Ser); MDH2, Somatic, c.26C>T (p.Ala9Val)
PatientID: 194
KindredID: 194
Case: Sex Unknown, 46Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0001732; HP:0002666; HP:0000107 (Hemangioblastoma, Abnormality of the pancreas, Pheochromocytoma, Renal cyst)
CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, pheochromocytoma and renal cystic lesion.
CaseNotHPOs: HP:0009711; HP:0006770 (Retinal capillary hemangioma, Clear cell renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1, S2 and S3
Variant: p.P59Rfs*8 (c.176del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA432536374, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.176del
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion; minus_1_frameshift_variant
CivicName: P59fs (c.176delC)
MultipleGeneVariants: N/A
PatientID: 259
KindredID: 259
Case: Sex Unknown, 29Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: None.
CasePresentingHPOs: HP:0001737, HP:0009711 (pancreatic cysts, retinal capillary hemangioma)
CaseHPOFreeText: N/A
CaseNotHPOs:HP:0002666, HP:0006770, HP:0000107, HP:0010797 (pheochromocytoma, clear cell renal cell carcinoma, renal cyst, hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1, S2, S3.
Variant: p.R167Q(c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q(c.500G>A)
MultipleGeneVariants: N/A
80 23 c.422_440del19 p.Asn141IlefsX12 x x De novo Parents -
PatientID: 80
KindredID: 80
Case: Sex Unknown, 23Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Parents were negative for the mutation. No phenotype details are noted for these family members.
CasePresentingHPOs: HP:0010797; HP:0000107 (Hemangioblastoma, Renal cyst)
CaseHPOFreeText: CNS hemangioblastoma and renal cystic lesion.
CaseNotHPOs: HP:0002666; HP:0006770; HP:0001732; HP:0009711 (Pheochromocytoma, Clear cell renal cell carcinoma, Abnormality of the pancreas, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1, S2 and S3
Variant: p.N141Ifs*12 (c.422_440del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA16621933, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.422_440del
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion; minus_1_frameshift_variant
CivicName: N141fs (c.422_440del)
MultipleGeneVariants: N/A
PatientID: 78
KindredID: 78
Case: Sex Unknown, 29Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family history noted but details not specified.
CasePresentingHPOs: HP:0001732 (Abnormality of the pancreas)
CaseHPOFreeText: Pancreatic cysts or tumors.
CaseNotHPOs: HP:0006770; HP:0002666; HP:0010797; HP:0009711; HP:0000107 (Clear cell renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Retinal capillary hemangioma, Renal cyst)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1, S2 and S3
Variant: p.C162W (c.486C>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: C162W (c.486C>G)
MultipleGeneVariants: N/A
GroupID: 85
Case: 27Y0M, Sex Unknown, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.538A>G) was found in 1 VHL family with a single patient.
CasePresentingHPOs: HP:0005584 (renal cell carcinoma)
CaseHPOFreeText: patient had RCCs diagnosed at 27Y
CaseNotHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma; cerebellar hemangioblastoma; pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.I180V (c.538A>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 161401 https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/
CAID: N/A
gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10191545-A-G
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: I180V (c.538A>G)
MultipleGeneVariants: N/A
GroupID: 50
DiseaseAssertion: assumed VHL
GroupSize: 5
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 5 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family
GroupPresentingHPOs: HP:0005584; HP:0006880; HP:0009711 (renal cell carcinoma; cerebellar hemangioblastoma; retinal capillary hemangioma)
GroupHPOFreeText: 4 patients had retinal angiomas diagnosed at a mean age of 27Y, and 3 had cerebellar hemangioblastomas diagnosed at a mean age of 32Y
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.R82_V84del (c.243_251delGCGCGTCGT)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA658820713 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.243_251del
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: R82_V84del (c.243_251del)
MultipleGeneVariants: N/A
GroupID: 60
DiseaseAssertion: VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)
GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 279.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.R161Q (c.482G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R161Q (c.482G>A)
MultipleGeneVariants: N/A
GroupID: 91
DiseaseAssertion: VHL
GroupSize: 4
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 4 members of this family were found to harbor the c.388G>C germline variant of the VHL gene. Member 6200 had no renal involvement. Member 6410 presented with mild renal disease. Members 5838 and 5839 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)
GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.V130L (c.388G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2229, https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: V130L (c.388G>C)
MultipleGeneVariants: N/A
GroupID: 394
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 3 members of this family were found to harbor a germline large rearrangement of the VHL gene. Member 9248 presented with moderate renal disease (RCC). Member 9313 and 2222 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)
GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 12 individuals with this mutation are reported. It is unclear which of the previously reported individuals correspond to which of the currently reported families/individuals (i.e. families 40, 90, 174, 237, 264, 284, 307 or 394).
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: Rearrangement
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: rearrangement_region
CivicName: Rearrangement
MultipleGeneVariants: N/A
PatientID: 18
KindredID: N/A
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S5 describes 8 patients with frameshift or in-frame deletions, including this patient.
Variant: p.F76del(c.224_226del)
LegacyVariant: c.437_439delTCT
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: F76del(c.224_226delTCT)
MultipleGeneVariants: N/A
PatientID: N/A
KindredID: 442
Case: Age unknown, Sex unknown, Ethnicity unknown
DiseaseAssertion: assumed VHL
FamilyInfo: Paper states: Germline, de novo (no clear confirmation)
CasePresentingHPOs: HP:0005584; HP:0010797 (renal cell carcinoma, hemangioblastoma)
CaseHPOFreeText: Bilateral RCC and a hemangioblastoma
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes (Specifically Supp. Table S2)
Variant: p.G144* (c.430G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223208 https://www.ncbi.nlm.nih.gov/clinvar/variation/223208/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: G144* (c.430G>T)
MultipleGeneVariants: N/A
Figure 1.
PatientID: II:5
KindredID: 1
Case: M, Age Unknown, Ethnicity Unknown
DiseaseAssertion: Asymptomatic
FamilyInfo: Look to proband (III:3) for extensive family info.
CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584 (Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Figure 1
Variant: p.P138= (c.414A>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: P138= (c.414A>G)
MultipleGeneVariants: N/A
c.496_506del11 (p.Val166Serfs*4) in seven individuals, belonging to two pedigrees.
PatientID: 44
KindredID: 44
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0006770 (hemangioblastoma; clear cell renal cell carcinoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0100634; HP:0030405; HP:0009711; HP:0030421 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 29437867 (likely family 17 - see here for more info)
SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.
Variant: p.V166Sfs*4 (c.496_506del11)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223229 https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_2_frameshift_variant
CivicName: V166Sfs*4 (c.496_506del)
MultipleGeneVariants: N/A
Case presentationFirst onsetA 19-years-old female was first found with occupation about 6.2 cm × 5.7 cm in the right adrenal five years ago based on CT scan at a regular physical examination, accompanied with fever and headache with high blood pressure. Tumor resection was performed, and pathological diagnosis was right pheochromocytoma. The patient was regularly subjected to follow-up.Secondary onsetDuring this hospitalization, CT scan found multiple tumor occupation in left adrenal and paraganglion region zones with round nodular shadows. Meanwhile, she had fever and headache with high blood pressure. Based on medical history and examination, she was diagnosed as left pheochromocytoma. Meanwhile, the occupying lesions in right lung and pancreas were found, located in extrabasal segment of inferior lobar and head respectively.Case characteristicsThe case characteristics were summarized: 1. A 12y female; 2. Tumor occupation was first found in right adrenal; 3. Tumor resection was performed and the pathological diagnosis was pheochromocytoma; 4. Multiple round nodular shadows were found in left adrenal and paraganglion region zones after five years; 6. The symptoms were fever and headache with high blood pressure; 7. The diagnosis was pheochromocytoma (PCC) and paraganglioma (PGL) (Combined PPGLs); 8. The occupying lesions located in right lung and pancreas were scanned and diagnosed with masses.Diagnostic methodThe patient was followed up regularly. Based on personal medical history, symptoms and imaging examinations, the patient was diagnosed as PPGLs combined with right lung and pancreas occupation.Multidisciplinary team discussion based on professional board indicated the following views: (1) The diagnosis was possibly considered as atypical VHL type II. Further qualitative diagnosis relied on genetic examination; (2) Other lesions like retina tumor should be examined. (3) PPGLs was surgically resected for pursuing pathological diagnosis. (4) The occupying lesions in right lung and pancreas were performed with puncture biopsy for further diagnosis. The diagnosis and treatment workflow were shown in Fig. 1.
PatientID: 1 (case)
KindredID: 1
Case: F, 19Y0M, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0006748; HP:0002666; HP:0030445; HP:0030405 (adrenal pheochromocytoma; pheochromocytoma; Pulmonary carcinoid tumor; Pancreatic endocrine tumor)
CaseHPOFreeText: At 12 years old, a female patient presented with fever and headache with high blood pressure. Upon a CT scan, a right adrenal tumor was detected and tumor resection was performed, revealing a pathological diagnosis of pheochromocytoma. Upon further review, a CT scan found multiple tumors in left adrenal and paraganglion region zones with round nodular shadows. She was diagnosed with pheochromocytoma (PCC) and paraganglioma (PGL). A lung puncture revealed a carcinoid and a pancreatic puncture indicates a neuroendocrine tumor. Left adrenalectomy and PPGL resection was performed and diagnosis was pathologically confirmed
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting:
PreviouslyPublished: N/A
SupplementalData: Yes (somatic info)
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.
GroupID: 43
DiseaseAssertion: VHL
GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A
GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.
GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0030393; HP:0001737; HP:0030405 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Pancreatic endocrine tumor)
GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (2), Retinal capillary hemangioma (4), Hemangioblastoma/brain/cerebellum (3), Endolymphatic sac tumor (2), Pancreatic cysts (3), Pancreatic endocrine tumor (1)
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplemental Table 2, Table 1, Table 3
Variant: Exon 1-3 Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: Germline, IRAK2, partial deletion
MultipleGeneVariants: Germline, ENST197804, partial deletion
We studied six patients with VHL disease and their relatives. Loss of heterozygosity (LOH) was determined by five flanking microsatellite polymorphic markers in the VHL locus
PatientID: 4
KindredID: F02
Case: F, Age Unknown, Taiwanese
DiseaseAssertion: Asymptomatic
FamilyInfo: A total of 2 members of this family (F02) had a complete deletion of the VHL gene. One of these patients (3) presented with clinical features of VHL.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Figure 1
Variant: Exon 1 Deletion (c.1-?_340+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Deletion of 53.3kb resulted in deletion of Exon 1 in the VHL gene.
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion
MultipleGeneVariants: Germline, FANCD2, deletion
p.Pro81Ser has been inherited from his healthy father (I.1)
PatientID: I.1
KindredID: 3
Case: M, Age Unknown, Ethnicity Unknown
DiseaseAssertion:Asymptomatic
FamilyInfo: The patient had a son who he passed this mutation to. The son (II.1) presented with hemangioblastoma and pancreatic cysts and had an additional de novo exon 1-3 deletion. Refer to figure 1, pedigree C for family information.
CohortInfo: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET/SDHB/SDHD/SDHC
PreviouslyPublished: May have been previously published in 11106358 and/or 7563486.
SupplementalData: Yes, File 1 for methods.
Variant: p.P81S(c.241C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/
CAID: N/A
gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: P81S(c.241C>T)
MultipleGeneVariants: N/A
97
Case#: 97, male, 66 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6517A>G
LegacyVariant:
ClinVar: No
CAID: CA414907348
gnomAD:
108
Case#: 108, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6870G>T
LegacyVariant:
ClinVar: No
CAID: CA414903147
gnomAD:
40
Case#: 40, male, 32 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 24.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.871G>A
LegacyVariant:
ClinVar: No
CAID: CA414918134
gnomAD:
117
Case#: 117, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5219+1G>A
LegacyVariant:
ClinVar: 993734
CAID: CA414913420
gnomAD:
152
Case#: 152, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2777delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
123
Case#: 123, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6273+1G>T
LegacyVariant:
ClinVar: No
CAID: CA414902680
gnomAD:
175
Case#: 175, male, 32 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.4%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons5_6
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
183
Case#: 183, male, 38 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons15_26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
101
Case#: 101, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6611T>C
LegacyVariant:
ClinVar: No
CAID: CA414906072
gnomAD:
73
Case#: 73, male, 67 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5422C>T
LegacyVariant:
ClinVar: 10278
CAID: CA255166
gnomAD:
164
Case#: 164, male, 43 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4339delG
LegacyVariant:
ClinVar: No
CAID: CA873341376
gnomAD:
24
Case#: 24, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6666G>A
LegacyVariant:
ClinVar: No
CAID: CA414905572
gnomAD:
142
Case#: 142, male, 22 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.599_601delAAG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
10
Case#: 10, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1596G>A
LegacyVariant:
ClinVar: No
CAID: CA414912044
gnomAD:
42
Case#: 42, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
166
Case#: 166, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379delA
LegacyVariant:
ClinVar: No
CAID: CA255151
gnomAD:
26
Case#: 26, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6976C>T
LegacyVariant:
ClinVar: 10085
CAID: CA255007
gnomAD:
36
Case#: 36, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.387G>C
LegacyVariant:
ClinVar: No
CAID: CA414919866
gnomAD:
139
Case#: 139, male, 17 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.dup exons7_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
115
Case#: 115, male, 37 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1271+1G>A
LegacyVariant:
ClinVar: 811704
CAID: CA414915622
gnomAD:
13
Case#: 13, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1861C>T
LegacyVariant:
ClinVar: No
CAID: CA414910596
gnomAD:
004–2009
Case#: 004-2009
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
003–2003
Case#: 003-2003
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
009–1006
Case#: 009-1006
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.822G>A
LegacyVariant:
ClinVar: No
CAID: CA255072
gnomAD:
071–2015
Case#: 071-2015
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2710dupC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–1037
Case#: 071-1037
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3169G>A
LegacyVariant:
ClinVar: No
CAID: CA255144
gnomAD:
020–2023
Case#: 020-2023
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5312T>C
LegacyVariant:
ClinVar: No
CAID: CA414910786
gnomAD:
002–2005
Case#: 002-2005
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.217T>C
LegacyVariant:
ClinVar: No
CAID: CA414920251
gnomAD:
060–2007
Case#: 060-2007
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
044–2001
Case#: 044-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.6344delT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–1038
Case#: 001-1038
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.6065G>A
LegacyVariant:
ClinVar: No
CAID: CA414904814
gnomAD:
038–1013
Case#: 038-1013
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
022–2004
Case#: 022-2004
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
001–2039
Case#: 001-2039
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5156T>C
LegacyVariant:
ClinVar: No
CAID: CA414913690
gnomAD:
015–2005
Case#: 015-2005
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
071–1015
Case#: 071-1015
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
035–2003
Case#: 035-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4825dupA
LegacyVariant:
ClinVar: No
CAID: CA255152
gnomAD: