Case#: 24

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 23/18%, Mild Phenotype, No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.5954G>A (p.Arg1985Gln)

ClinVar: 618098 https://www.ncbi.nlm.nih.gov/clinvar/variation/618098/

CAID: CA414905715

gnomAD: MAF for Arg1985Gln in the European (non-Finnish) population 0.00001224<br> https://gnomad.broadinstitute.org/variant/X-154132225-C-T?dataset=gnomad_r2_1

Case#: 11

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.1336C>T (p.Arg446Ter)

ClinVar: 10145 https://www.ncbi.nlm.nih.gov/clinvar/variation/10145/

CAID: CA255038

gnomAD: Not reported

Case#: 23

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.5953C>T (p.Arg1985Ter)

ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/

CAID: CA255191

gnomAD: Not reported

Case#: 37

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 36%, Mild Phenotype, No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.6977G>A (p.Arg2326Gln)

ClinVar: 10126 https://www.ncbi.nlm.nih.gov/clinvar/variation/10126/

CAID: CA255027

gnomAD: Not reported

Case#: 1

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 21% (Mild Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.197A>T (p.Lys66Ile)

ClinVar: NA

CAID: CA414920295

gnomAD: Not reported

Case#: 21

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C <=1% (Severe Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.5213del

ClinVar: NA

CAID: CA1139532038

gnomAD: Not reported

Case#: 47

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C 18/26% (Mild Phenotype)

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F9

Variant: NM_000133.3(F9):c.835G>A (p.Ala279Thr)

ClinVar: 216926 https://www.ncbi.nlm.nih.gov/clinvar/variation/216926/

CAID: CA277507

gnomAD: Not reported

Case#: 4

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 3/5/3% (Moderate Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.541G>A (p.Val181Met)

ClinVar: 10177 https://www.ncbi.nlm.nih.gov/clinvar/variation/10177/

CAID: CA255066

gnomAD: Not reported

Case#: 22, Female HA carrier

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 60%, Mild Phenotype, No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.5374-19del

ClinVar: 439679 https://www.ncbi.nlm.nih.gov/clinvar/variation/439679/

CAID: CA10567985

gnomAD: MAF in the South Asian population 0.3867<br>https://gnomad.broadinstitute.org/variant/X-154133316-CA-C

Case#: 19

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.4692del (p.Leu1566Ter)

ClinVar: NA

CAID: CA1139532037

gnomAD: NA

Case#: 038-2012

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.1834C>T

LegacyVariant:

ClinVar: No

CAID: CA255129

gnomAD:

Case#: 002-2010

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.901C>T

LegacyVariant:

ClinVar: No

CAID: CA414917990

gnomAD:

Case#: 035-2005

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.1175C>T

LegacyVariant:

ClinVar: No

CAID: CA255095

gnomAD:

Case#: 068-2003

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:

Case#: 004-2013

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.6046C>T

LegacyVariant:

ClinVar: No

CAID: CA255197

gnomAD:

Case#: 001-2052

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.1988C>T

LegacyVariant:

ClinVar: No

CAID: CA255135

gnomAD:

Case#: 060-2008

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.1618C>A

LegacyVariant:

ClinVar: No

CAID: CA414911950

gnomAD:

Case#: 020-2015

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.5612T>G

LegacyVariant:

ClinVar: No

CAID: CA414908197

gnomAD:

Case#: 004-2025

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.328A>G

LegacyVariant:

ClinVar: No

CAID: CA255057

gnomAD:

Case#: 001-2049

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.901C>T

LegacyVariant:

ClinVar: No

CAID: CA414917990

gnomAD:

Case#: 045-2002

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.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 003-2012

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.992T>C

LegacyVariant:

ClinVar: No

CAID: CA414917621

gnomAD:

Case#: 020-2052

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.923C>T

LegacyVariant:

ClinVar: No

CAID: CA255082

gnomAD:

Case#: 003-2007

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.1475A>G

LegacyVariant:

ClinVar: No

CAID: CA337334224

gnomAD:

Case#: 087-2003

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.5122C>T

LegacyVariant:

ClinVar: No

CAID: CA120919

gnomAD:

Case#: 020-2045

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.458A>T

LegacyVariant:

ClinVar: No

CAID: CA414919676

gnomAD:

Case#: 084-2006

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.1910A>G

LegacyVariant:

ClinVar: No

CAID: CA414909849

gnomAD:

Case#: 001-2045

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.1462G>A

LegacyVariant:

ClinVar: No

CAID: CA414912862

gnomAD:

Case#: 038-2020

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.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 035-2017

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.1834C>T

LegacyVariant:

ClinVar: No

CAID: CA255129

gnomAD:

Case#: B83

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C Chr = 17, FVIII:AG = 19, inverse assay discrepancy present (OSA<CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.6448G>A

LegacyVariant:

ClinVar: No

CAID: CA414907951

gnomAD:

Case#: A14, A15

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 15, FVIII:AG = 41, assay discrepancy present (OSA>CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.5530C>T

LegacyVariant:

ClinVar: No

CAID: CA255170

gnomAD:

Case#: B79 - B82

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 15, inverse assay discrepancy present (OSA<CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.6413C>A

LegacyVariant:

ClinVar: No

CAID: CA255204

gnomAD:

Case#: B28, B29

DiseaseAssertion: NA

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C Chr = 78, FVIII:AG = 94, inverse assay discrepancy present (OSA<CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.2089G>C

LegacyVariant:

ClinVar: No

CAID: CA414909014

gnomAD:

Case#: A4

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 6, FVIII:AG = 15, assay discrepancy present (OSA>CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.896A>T

LegacyVariant:

ClinVar: No

CAID: CA255078

gnomAD:

Case#: 30

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Mild

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.6857A>G (p.Asp2267Gly)

ClinVar: NA

CAID: CA414903332

gnomAD: Not reported

Case#: 28

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Mild

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.6427A>G (p.Met2124Val)

ClinVar: NA

CAID: CA414899297

gnomAD: Not reported

Case#: 23

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Moderate

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.1910A>T (p.Asn618Ile)

ClinVar: NA

CAID: CA414909847

gnomAD: Not reported

Case#: 8

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.5805T>A (p.Tyr1935Ter)

ClinVar: NA

CAID: CA414906924

gnomAD: Not Reported

Case#: 1

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.1251_1252insC (p.Val418ArgfsTer6)

ClinVar: NA

CAID: CA1139532040

gnomAD: Not reported

Case#: UQU-HB3, Male, 1-months-old, Saudi Arabia

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe, PTT 50.9, Disabled left ankle

CasePreviousTesting: Screened for all factor IX exons by capillary sequencing

Gene: F9

Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)

ClinVar: NA

CAID: CA414441211

gnomAD: Not reported

Case#: UQU-HB9, Male, 1-months-old, Saudi Arabia

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Moderate, PTT 51.4, Unable to flex knees fully

CasePreviousTesting: Screened for all factor IX exons by capillary sequencing

Gene: F9

Variant: NM_001313913.1:c.580G>A

ClinVar: NA

CAID: CA414441211

gnomAD: Not reported

Case#: UQU-HB11, Male, 1-months-old, Saudi Arabia

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0001892 (Abnormal bleeding)

CaseHPOFreeText: Severe, Unable to flex elbows fully, PTT 148.3

CasePreviousTesting: Screened for all factor IX exons by capillary sequencing

Gene: F9

Variant: NM_000133.4(F9):c.855G>C (p.Glu285Asp)

ClinVar: 828138 https://www.ncbi.nlm.nih.gov/clinvar/variation/828138/

CAID: CA414444506

gnomAD: Not reported

Case: IP #30

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 28

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4151T>G p.Leu1384Arg

HGVS:

ClinVarID: not found

CAID: CA383504381

gnomAD: absent

Case: IP #35

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 24

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4517C>T p.Ser1506Leu

HGVS:

ClinVarID: 100369

CAID:

gnomAD: absent

Case: IP #16

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 78

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3433C>T p.Arg1145Cys

HGVS:

ClinVarID: not found

CAID: CA383511379

gnomAD: absent

Case: IP #56

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 60

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: 7 (also in row 2 splice variants table 6)

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 31

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2546+1G > A

HGVS:

ClinVarID: not found

CAID: CA383520269

gnomAD: 0.000001239 (2 in 1614166) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036387-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.5092G > T p.Gly1698Cys

CAID: CA383496674

gnomAD: 6.196e-7 (1 in 1613980) no homozygotes https://gnomad.broadinstitute.org/variant/chr12-6016832-C-A?dataset=gnomad_r4

Case: IP #27 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 69

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3673T>G p.Cys1225Gly

HGVS:

ClinVarID: 100272

CAID:

gnomAD: absent

Case: IP #40

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4690C>T p.Arg1564Trp

HGVS:

ClinVarID: 811702

CAID:

gnomAD: 0.000006818 (11 in 1613330) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018728-G-A?dataset=gnomad_r4

Case: IP #26 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 23

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #30 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 27

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: 8 (also in row 21 table 6)

DiseaseAssertion: type 2A/2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 16; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 12

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.4811T>A p.Val1604Asp

CAID: CA383499144

gnomAD: absent

Case: IP #24 in type 2N VWD sub-cohort (also in row 5 splice variants table 6)

DiseaseAssertion: type 2N/1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 34; FVIII:C [IU/dL] = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.6798+2T>A

ClinVarID: 1803122

gnomAD: absent

Case: IP #13 (also in row 7 table 6)

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 45

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3314C>A p.Ala1105Asp

HGVS:

ClinVarID: 626953

CAID:

gnomAD: absent

Case: IP #67

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 9,3; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 41

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.7988G>C p.Arg2663Pro

HGVS:

ClinVarID: 372760

CAID:

gnomAD: 0.001352 (2181 in 1613616) 4 homozygotes https://gnomad.broadinstitute.org/variant/12-5952518-C-G?dataset=gnomad_r4

Case: IP #42 in type U VWD sub-cohort (also in row 26 table 6)

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 9; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 41

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.7645T>C p.Cys2549Arg

HGVS:

ClinVarID: not found

CAID: CA383489376

gnomAD: absent

Case: IP #22 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = 27; FVIII:C [IU/dL] = 95

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4022G>A p.Arg1341Gln

HGVS:

ClinVarID: 291

CAID:

gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.5801T>G p.Val1934Gly

ClinVarID: 627336

gnomAD: 0.00006260 (101 in 1613356) no homozygotes https://gnomad.broadinstitute.org/variant/12-6011658-A-C?dataset=gnomad_r4

Case: 2

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 34

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.-2522C>T

HGVS:

ClinVarID: not found

CAID: not found

gnomAD:

MultipleGeneVariants:

Gene: VWF

Variant: c.3586T>C

ClinVarID: 100270

Case: IP #65

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 33; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4912G>A p.Glu1638Lys

HGVS:

ClinVarID: 100403

CAID:

gnomAD: absent

Case: IP #37 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 25

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4241T>G p.Val1414Gly

HGVS:

ClinVarID: 619752

CAID:

gnomAD: absent

Case: IP #2 in type 2M VWD sub-cohort (also in row 12 table 6)

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 70; VWF:CB (IU/dL) = 38

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3847G>A p.Asp1283Asn

HGVS:

ClinVarID: not found

CAID: CA383506815

gnomAD: absent

Case: IP #10 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 73; VWF:Ac [IU/dL] = 23; FVIII:C [IU/dL] = 79; VWF:CB (IU/dL) = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4195C>T p.Arg1399Cys

HGVS:

ClinVarID: 100337

CAID:

gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4

Case: IP #23 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1/M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 14

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro

HGVS:

ClinVarID: 2438545

CAID:

gnomAD: absent

Case: IP #10 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 18; FVIII:C [IU/dL] = 55

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3586T>C p.Cys1196Arg

HGVS:

ClinVarID: 100270

CAID:

gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4

Case#: 35003, Age 75, Female, Blood Type A- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members in Family# 3502.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 6.6, VWF:RCo: 8.5, FVIII:C:13, VWF:CB: 11

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 2

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 13001, Age 61, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient was the only member of Family# 1301.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 27, VWF:Ag: 11, VWF:RCo: 9.7, FVIII:C: 36, VWF:CB: 12

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.7985A>G

ClinVar: N/A

CAID: CA383487641 CAID

gnomAD: N/A

Case#: 02042, Age 41, Male, Blood Type: O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Family#: 0215; 5 Members of the family were included in the study. 1 was diagnosed type 3 (patient 02039) and the other 4 were carriers for VW

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:Ag: 25, VWF:RCo: 21, FVIII:C:77, VWF:CB: 27

CaseNotHPOs:

CaseNotHPOFreeText: Bleeding score 1

Protein Expression:

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.1109G>A

ClinVar: N/A

CAID:CA6403559

CAID

gnomAD: MAF of 0.000008802 (1/113608 alleles) in the European (non-Finnish population). gnomAD

Case#: 02074, Age 37, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #0228.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 24, VWF:RCo: 21, FVIII:C: 111, VWF:CB: 29

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4(VWF):c.3426T>C (p.Cys1142=), NM_000552.4:c.6254G>T (p.Cys2085Phe), and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)

ClinVar: 256668 and 619934 ClinVar ClinVar2

CAID: CA6402757, CA383492060, and CA658683073

CAID1

CAID2

gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).

Case#: 27032, Age 49, Female, Blood Type O+

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#2716. The other member has the same variant, but is only a carrier.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:31, VWF:RCo: 22.7, FVIII:C: 72, VWF:CB: 38

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2518G>T (p.Glu840Ter)

ClinVar: N/A

CAID:CA383520331 CAID

gnomAD: N/A

Case#: 06012, Age 10, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is member of Family# 0609, which includes 3 individuals. All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 10, VWF:Ag: 13, VWF:RCo:14, FVIII:C:40, VWF:CB:13

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3363G>T (p.Arg1121Ser)

ClinVar: N/A

CAID: CA383511875 CAID

gnomAD: N/A

Case#: 02064, Age 32, Male, Blood type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is a part of family # 0224. There are 3 other members of the family (02065, 02066, 02067). All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 13, VWF:Ag: 4.7, VWF:RCo: 5, FVIII:C: 16, VWF:CB:6

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene:VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308

ClinVar

CAID: CA114160

CAID1

gnomAD: N/A

Case#: 27024, Age 56, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2713.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:5.3, VWF:RCo:6, FVIII:C:38, VWF:CB:4.2

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 06024, Age 36, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#0617.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 1, VWF:Ag:35, VWF:RCo:25, FVIII:C:69, VWF:CB: 27

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.7300C>T (p.Arg2434Ter)

ClinVar: 100464 ClinVar

CAID: CA228781 CAID

gnomAD: MAF of 0.0001298 (2/15414 alleles) in the European (non-Finnish) population. gnomAD

Case#: 02058, Age 64, Female, Blood type A+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of family #0221.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 19, VWF:Ag: 7.3, VWF:RCo: 5.9, FVIII:C: 19, VWF:CB: 6.3

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 03035, Age 51, Male (Table S3)

Disease Assertion: VWD1

FamilyInfo: A part of family #03150 along with two other patients.

Parental Genotype: Not listed

CasePresentingHPOs: Not listed

CaseHPOFreeText: Bleeding Score 4, VWF:Ag: 34, VWF:RCo: 26, FVIII:C: 43, VWF:CB 33

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 32002, Age 49, Female, Blood Type +

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 3202.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 34, VWF:RCo: 30, FVIII:C: 53, VWF:CB: 29

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.7408C>T (p.Gln2470Ter)

ClinVar: 100469 ClinVar

CAID: CA228790 CAID

gnomAD: MAF of 0.00002891 (1/34590 alleles) in the Latino population.

Case#: 06007, Age 54, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD

FamilyInfo: Two total patients were documented from family# 0606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 28, VWF:RCo: 26.1, FVIII:C: 56, VWF:CB: 23

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.1156+2T>C (intronic)

ClinVar: N/A

CAID: CA383504978 CAID

gnomAD: N/A

Case#: 18001, Age 50, Male, Blood Type B+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient one of 3 members of Family#1801. All of the patients have the same variant.

Parental Genotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:10, VWF:RCo:6.1, FVIII:C:17, VWF:CB:8.2

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His) and NM_000552.4:c.6989T>G (p.Val2330Gly)

ClinVar: 308 ClinVar1

CAID: CA114160 and CA6401808 CAID1 CAID2

gnomAD: MAF of 0.000008823 (1/113342 alleles) in the European (non-Finnish population) (CA6401808) gnomAD

Case#: 36008, Age 34, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag: 34, VWF:RCo:14, FVIII:C: 37, VWF:CB: 25

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2771G>A(p.Arg924Gln) and NM_000552.4:c.3390C>T (p.Cys1130=)

ClinVar: 627186 ClinVar

CAID: CA228368 and CA478101454 CAID1 CAID2

gnomAD: MAF of 0.01866 (2411/ 129182 alleles) in the European (non-Finnish) population (CA228368). gnomAD

Case#: 02052, Age 25, Male, Blood type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only family member of family # 0220

Parental Genotype: Not listed

CasePresentingHPOs:N/A

CaseHPOFreeText: Bleeding Score: 11, VWF:Ag: 15, VWF:RCO:12, FVIII:C:20, VWF:CB: 16

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.1625C>G (p.Ala542Gly) and NM_000552.4:c.6187C>T (p.Pro2063Ser)

ClinVar: 381621 and 100436 ClinVar1

ClinVar2

CAID: CA6403319 and CA202650 CAID1

CAID2

gnomAD: MAF of 0.001355 (48/ 35418 alleles) in the Latino population (CA6403319). MAF of 0.04854 (1486/ 30616 alleles) in the South Asian Population (CA202650).

gnomAD1

gnomAD2

Case: Row 11 in Supplemental Table 1. Data represents 2 patients from 2 families.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.0; VWFpp/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1625C>G A542G

HGVS: VWF:c.1625C>G (p.Ala542Gly)

ClinVarID: 381621

CAID:

gnomAD: 0.001062 (1714 in 1613708) 2 homozygotes https://gnomad.broadinstitute.org/variant/12-6057953-G-C?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.8366C>T p.Thr2789Ile (only present in 1 of the 2 patients)

CAID: CA6401321

gnomAD: absent

Case: Row 14 in Supplemental Table 1.

DiseaseAssertion: type 3 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 5.8; VWFpp/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1992delC C665A fs*3

HGVS: VWF:c.1992del (p.Cys665AlafsTer3)

ClinVarID: 1695349

CAID:

gnomAD: 6.195e-7 (1 in 1614124) no homozygotes https://gnomad.broadinstitute.org/variant/12-6052736-AG-A?dataset=gnomad_r4

Case: 2M-2

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.01; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.41

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1409710

Gene: VWF

Variant: c.3970G>A (p.Gly1324Ser)

HGVS: NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)

ClinVarID: 300; https://www.ncbi.nlm.nih.gov/clinvar/variation/300/?new_evidence=false

CAID:

gnomAD: MAF = 0.00003267 in South Asian population; https://gnomad.broadinstitute.org/variant/12-6128614-C-T

Case: 2A-5

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.24

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 1537829

Gene: VWF

Variant: c.4789C>T (p.Arg1597Trp)

HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)

ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-5

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.32; AcuStar CB/Ag = 0.19; ELISA CB/Ag = 0.38

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2B-8

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.99; AcuStar CB/Ag = 1.35; ELISA CB/Ag = 1.02

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 16985174

Gene: VWF

Variant: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/?new_evidence=false

CAID:

gnomAD: MAF (European, Finnish) = 0.003667; 1 homozygote; https://gnomad.broadinstitute.org/variant/12-6128787-G-A

Case: 2A-7

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.27; AcuStar CB/Ag = 0.10; ELISA CB/Ag = 0.39

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID:1673047

Gene: VWF

Variant: c.4883T>C (p.Ile1628Thr)

HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-1

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.49; AcuStar CB/Ag = 0.29; ELISA CB/Ag = 0.33

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

Variant: c.4541T>G (p.Phe1514Cys)

HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)

ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-2

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.62; AcuStar CB/Ag = 0.50; ELISA CB/Ag = 0.47

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case#: 32 year old female

DiseaseAssertion: VWD Type 2M

CaseHPOFreeText4: Testing was repeated multiple times, with initial results being untrustworthy. Follow up testing is as follows: VWF:RCo/VWF:Ag ratio = 0.61, VWF:CB = 10. Normal multimers

CasePreviousTesting: Molecular analysis by next generation gene sequencing analysis of VWF, F8, GPIBA and GPIBB.

Gene: VWF

Variant: variant in VWF at exon 31 (c.5347 T > G) that leads to a VWF protein change of p.Ser1783Ala

HGVS: NM_000552.5(VWF):c.5347T>G (p.Ser1783Ala)

ClinVar: 31012

CAID: CA228715

gnomAD: 0.0006918 in South Asian pop

Case UZ092: 28 year old female (row 93 in supplementary table)

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442

CaseHPOFreeRext: vWF:Ag (%) = 16; vWF:GPIbR (%) = 12; Act/Ag ratio = 0.75; FVIII:C (%) = 28; Platelets (x10^9/L) = 288

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.4135C>T p.Arg1379Cys

HGVS:

ClinVarID: 100333

CAID:

gnomAD: 0.00002540 (41 in 1613910) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019283-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: F11

Variant: c.1305-2A>G

ClinVarID: 2572126

gnomAD: absent

Case 13: 40 year old male, study ID UZ094 in supplemental table

DiseaseAssertion: type 2 NOS VWD presequencing, type 2M VWD postsequencing

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442

CaseHPOFreeRext: vWF:Ag (%) = 61.2; vWF:GPIbR (%) = 24.8; Act/Ag ratio = 0.41; FVIII:C (%) = 31.5; Platelets (x10^9/L) = 368; normal multimers

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.4195C>T p.Arg1399Cys

HGVS:

ClinVarID: 100337

CAID:

gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4

Case: 55-year-old Italian, male

DiseaseAssertion: VWD, Type 2B

FamilyInfo: Patient did not report any family history of bleeding and his daughter did not show any menorrhagia and hemorrhagic disorder. Genotyping for daughter was negative for variants of interest. Paternity of daughter established. Testing performed on both daughter and wife.

ParentalGenotype(s): No genotyping available on parents, as they were deceased.

CasePresentingHPOs: HP:0000421, HP:0004846, HP:0012147, HP:0030129, HP:0030130, . HP:0030132, HP:0011871, HP:0003645

CaseHPOFreeRext: aPTT,s=45.4, Fibrinogen,mg/dL=349, VFG:Ag, IU/dL=23.4, VWF:RCo, IU/dL=8.5, VWF:CBA, IU/dL=7.2, FVIII:C, IU/dL=28.2, VWFpp, %=63.4, VWF:RCo/VWF:Ag =0.36, VWF:CBA/VWF:Ag=0.31, VWFpp/VWF:Ag=2.7, FVIII/VWF:Ag=1.2,FVIII/VWF:binding, %=127.8, ADAMTS-13 act, U/dL=110.1, Platelets, ×109/L=121-166, Hb, g/dL=8.1-15.1, Blood group= A-Rh +Rh phenotype: ccDEe Kell/Cellano phenotype: kk

CaseNOTHPOs: none

CaseNOTHPOFreeText: none

CasePreviousTesting: none

GenotypingMethod: Molecular genetic analysis of the VWF gene was performed using 3100-Avant Genetic Analyzer. Sanger-sequencing procedures were carried out to validate the identified genetic variants.

PreviouslyPublished:

1) PMID: 27007659

2) PMID: 20492463

Gene: VWF

Variant:

1) c.2771G>A p.R924Q, exon 21, D′D3 domain,cis heterozygous

2) c.6532G>T p.A2178S, exon 37, cis heterozygous

HGVS:

1) NC_000012.12:g.6031493C>T, NC_000012.11:g.6140659C>T, NG_009072.2:g.98178G>A, NM_000552.5:c.2771G>A, NM_000552.4:c.2771G>A, NM_000552.3:c.2771G>A, XM_047429501.1:c.2771G>A, NP_000543.3:p.Arg924Gln, XP_047285457.1:p.Arg924Gln

2) NC_000012.12:g.5993928C>A, NC_000012.12:g.5993928C>T, NC_000012.11:g.6103094C>A, NC_000012.11:g.6103094C>T, NG_009072.2:g.135743G>T, NG_009072.2:g.135743G>A, NM_000552.5:c.6532G>T, NM_000552.5:c.6532G>A, NM_000552.4:c.6532G>T, NM_000552.4:c.6532G>A, NM_000552.3:c.6532G>T, NM_000552.3:c.6532G>A, XM_047429501.1:c.6532G>T, XM_047429501.1:c.6532G>A, NP_000543.3:p.Ala2178Ser, NP_000543.3:p.Ala2178Thr, XP_047285457.1:p.Ala2178Ser, XP_047285457.1:p.Ala2178Thr

ClinVarID:

1) 100240

2) 619942

CAID:

1) CA228368

2) CA6401974

gnomAD:

1) European (non-Finnish) 0.02225 https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4

2) European (non-Finnish) 0.02318 https://gnomad.broadinstitute.org/variant/12-5993928-C-A?dataset=gnomad_r4

Case1:

DiseaseAssertion: Hypertrophic cardiomyopathy

CaseHPOFreeText: severe congestive heart failure

GenotypingMethod: bi-directional Sanger sequencing

Variant: NM_000257.4:c.2191C>T

ClinVar: 181176

CAID: CA011922

gnomAD: not found

Case1: n/a

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened.

Variant: NM_000257.4:c.3158G>A

ClinVar: 155814

CAID: CA013417

gnomAD: https://gnomad.broadinstitute.org/variant/14-23891476-C-T

0.0006368 European - Finnish

Case#: SF No. 28, GC Case No. 21, male, 83

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: No

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric 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

Case#: SF No. 30, GC Case No. 23, female, 31

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: Yes, one affected

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric 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 Table S3

Case: 210

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.1021T>C (p.Phe341Leu)

CAID: CA389051533 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051533

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYH6 Variant

Variant: NM_002471.3:c.5209A>T (p.Thr1737Ser)

CAID: CA257777730 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257777730

gnomAD: Not in gnomAD

(2) VCL Variant

Variant: NM_014000.2(VCL):c.1907A>G (p.His636Arg)

ClinVar: 45594 https://www.ncbi.nlm.nih.gov/clinvar/variation/45594/

gnomAD: 0.006330, https://gnomad.broadinstitute.org/variant/10-75860740-A-G

Supplementary Data Table S3

Case: 329

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

Supplementary Data Table S3

Case: 154

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) FBN1 Variant

Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)

ClinVar: 199948 https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/

gnomAD: 0.006608, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

(2) JUP Variant

Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)

ClinVar: 45842 https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/

gnomAD: 0.01341, https://gnomad.broadinstitute.org/variant/17-39913771-C-T

Supplementary Data Table S3

Case: 204

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

Supplementary Data Table S3

Case: 145

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

MultipleGeneVariants:

(1) 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

(2) 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

Supplementary Data Table S3

Case: 355

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.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

gnomAD: 0.001416, https://gnomad.broadinstitute.org/variant/14-23892910-A-G

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3413G>A (p.Arg1138His)

ClinVar: 177689 https://www.ncbi.nlm.nih.gov/clinvar/variation/177689/

gnomAD: 0.01063, https://gnomad.broadinstitute.org/variant/11-47354442-C-T

Supplementary Data Table S3

Case: 52

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.2451C>A (p.Asn817Lys)

ClinVar: 235029, https://www.ncbi.nlm.nih.gov/clinvar/variation/235029/

gnomAD: absent

MultipleGeneVariants:

(1) 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: absent

Supplementary Data Table S3

Case: 19

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

Supplementary Data Table S3

Case: 256

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.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

MultipleGeneVariants:

(1) PLB1 Variant

Variant: NM_153021.4:c.275A>G (p.Lys92Arg)

CAID: 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

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995 https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.02090, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Data Table S3

Case: 353

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) EYA4 Variant

Variant: NM_004100.5(EYA4):c.979G>A (p.Asp327Asn)

ClinVar: 191664 https://www.ncbi.nlm.nih.gov/clinvar/variation/191664/

gnomAD: 0.004341, https://gnomad.broadinstitute.org/variant/6-133802609-G-A

(2) TTN Variant

Variant: NM_133378.4:c.21031G>T (p.Glu7011Ter)

CAID: CA349496727 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_133378.4%3Ac.21031G%3ET

gnomAD: Not in gnomAD