Annotating here since the article is a PDF.

Case#: Lin ERT Proband, 3yo at dx, male, Taiwan

DiseaseAssertion: MPS1 H/S

FamilyInfo:

CasePresentingHPOs: HP:0002094, HP:0030828, HP:0002870, HP:0001640, HP:0001712, HP:0005133, HP:0001654, HP:0005145, HP:0008155, HP:0002653, HP:0002829, HP:0001376, HP:0002751, HP:0004348, HP:0007957, HP:0007663, HP:0002167, HP:0032341, HP:0410042

CaseHPOFreeText: Positive urine MPS screening test, blood IDUA activity=0.4 umol/h per mg protein (normal range 10-35). ERT improved cardiopulmonary status, joint range of motion, mobility, bone and joint pain, kyphoscoliosis, bone mineral density, sleep quality, corneal clouding and visual acuity, speech fluency, forced vital capacity and liver size, and resulted in 80.2% reduction in urinary GAG excretion. Cardiopulmonary failure

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: T364M homozygous

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Case#: ATM02_V-3

Demographics: Male, 18 yrs at report

CasePresentingHPOs: HP:0000752, HP:0001581

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod:

Variant: NM_017890.4:c.6879delT

ClinVar:

CAID: CA4824093

gnomAD:

VariantEvidence: This variant has been reported in two apparently unrelated families of common ethnicity, and therefore likely founder mutation. Hence, the score is reduced from default.

CaseAddInfo:

CasePMIDs:

Case: Family H Proband HII-2, female, 50yo at report

CasePresentingHPOs: HP:0000823, HP:0002240, HP:0001822, HP:0034373, HP:0100490, HP:0002619, HP:0000520, HP:0001838, HP:0007380, HP:0001084, HP:0001871, HP:0004322, HP:0000135, HP:0000141, HP:0012410, HP:0011974

CasePresentingHPOsFreeText: stasis ulcers

CaseNOTHPOs: HP:0000953, HP:0000998, HP:0030053, HP:0001256

CaseNOTHPOSFreeText: dilated lateral scleral vasculature

CasePreviousTesting: Direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: Microarray, homozygosity mapping, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: Consanguineous parents, not genotyped. 3 unaffected, not genotyped siblings

PreviouslyPublished: n/a

VariantEvidence: Functional characterization of G437R in Xenopus oocytes showed that transport activity was approximately half of WT SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to WT, suggesting decreased stability (Kang et al. 2010; PMID: 20595384)

Case: Family C Proband CII-2, male, Arabic, Israeli, 32yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0008064, HP:0001433, HP:0001634, HP:0001935, HP:0033211, HP:0003565, HP:0000027, HP:0100324, HP:0002716, HP:0100727, HP:0001084

CasePresentingHPOsFreeText: scrotal masses, Testicular ultrasound examination done in patient C2 revealed echogenic thickening of both the spermatic cords and the scrotal sac, normal-sized testes with a few microcalcifications; extreme infiltration of the subcutis in the lower abdominal wall and thighs was noted in patient C2 by computed tomography scan; nonspecific inflammatory infiltrates in the portal spaces on liver biopsy; nonspecific pathological deviations on bone marrow biopsy

CaseNOTHPOs: HP:0000054, HP:0002619, HP:0000365, HP:0000520, HP:0012385, HP:0007380

CaseNOTHPOSFreeText: dilated scleral vessels

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous, heterozygous parents. brother (CII-4) is also genotype/phenotype +

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

Case: Family D Proband DII-2, male, Arabic, Israeli, 33yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0008064, HP:0000054, HP:0000771, HP:0001433, HP:0002619, HP:0001684, HP:0001634, HP:0000365, HP:0000520, HP:0007380, HP:0001935, HP:0003565, HP:0008734, HP:0000027, HP:0002716, HP:0100727, HP:0100324

CasePresentingHPOsFreeText: scrotal masses, thickened scrotal sac, retracted penis, nonspecific inflammatory infiltrates in the portal spaces on liver biopsy

CaseNOTHPOs: HP:0012385

CaseNOTHPOSFreeText: Dilated scleral vessels

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous, heterozygous parents. brothers (DII-5 and DII-7) are also genotype/phenotype +. brothers (DII-8, DII-9, and DII-11) are het and unaffected. brother DII-10 was affected but deceased so no genotype recorded

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

CaseP6 male, 28yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0003251

(reduced sperm motility, male infertility)

HPOsFreeText Patient's sperm volume: 3mL(lower reference limit: 1.5), sperm concentration: 7.8million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), normal spermatozoa: 0%(reference: 4).

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP5 male, 31yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 3.4mL(lower reference limit: 1.5), sperm concentration: 60million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), vitality: 62%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 80%, abnormal head morphology: 8%, abnormal base: 2%, absent flagella: 24%, short flagella: 50%, coiled flagella: 8%, flagella of irregular caliber: 68%, multiple anomalies index: 2.5%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo nonconsanguineous

CasePMIDs 29449551

CaseP4 male, 45yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 2.2mL(lower reference limit: 1.5), sperm concentration: 56million/mL(reference: 15), total motility after 1hr: 0%(reference: 40), vitality: 79%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 78%, abnormal head morphology: 58%, abnormal base: 14%, absent flagella: 50%, short flagella: 32%, coiled flagella: 34%, flagella of irregular caliber: 50%, multiple anomalies index: 3.4%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomaD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP3 male, 51yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 1.7mL(lower reference limit: 1.5), sperm concentration: 56million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), vitality: 73%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 56%, abnormal head morphology: 20%, abnormal base: 32%, absent flagella: 22%, short flagella: 59%, coiled flagella: 27%, flagella of irregular caliber: 37%, multiple anomalies index: 2.7%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP2 male, 54yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 1.8mL(lower reference limit: 1.5), sperm concentration: 6million/mL(reference: 15), total motility after 1hr: 1%(reference: 40), vitality: 80%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 56%, abnormal head morphology: 10%, abnormal base: 2%, absent flagella: 6%, short flagella: 32%, coiled flagella: 17%, flagella of irregular caliber: 68%, multiple anomalies index: 2.3%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD n/a

CaseAddInfo consanguinity

CasePMIDs 29449551

PMID: 28132693

Gene: ARHGEF18

Disease: Retinitis pigmentosa

MonDO ID: MONDO:0019200

Case# HondaF, female, newborn

CasePresentingHPOs HP:0001640, HP:0006682, HP:0011713, HP:0100572

CaseGenotypingMethod "gene analysis"

Variant NC_000003.10:g.14147425G>A

CAID CA052413

gnomAD 0.001044 link

CaseAddInfo 2 mutations in cis from mom, phenotypes described at birth (usually adult onset)

PMID: 14583446

Gene: GALNS

Disease: mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case: Family C/Prendiville Patient 2, Lebanese-Australian, 11yo at report

Not scoring this proband since this variant has been reported many times already and parents are consanguineous, from Lebanon which is near many of the other cases

Case: Family B/Prendiville Patient 3, Lebanese-Australian, 11yo at report

CasePresentingHPOs: HP:0000343, HP:0030084, HP:0001953, HP:0100651, HP:0003237, HP:0030166, HP:0003326, HP:0002829, HP:0002315, HP:0002027, HP:0000998, HP:0000520, HP:0001433, HP:0002594, HP:0002171, HP:0100578, HP:0001999, HP:0100534, HP:0001763, HP:0003565

CasePresentingHPOsFreeText: Inflammatory symptoms. Decreased IgM. Onset of hyperpigmentation at 2-3mo; located on upper thigh and scrotum. Right frontal lobe gliosis. Lipoatrophy of lower legs.

CaseNOTHPOs: HP:0004322, HP:0001738, HP:0002926

CaseNOTHPOSFreeText: Autoantibodies to pancreatic islet cells.

CasePreviousTesting: ADAMTS14, C10orf27, CDH23, EIF4EBP2, LRRC2, KIAA1274, NODAL, NPFFR1, PCBD1, PPA1, PRF1, SLC29A3, SGPL1, UNC5B were sequenced since they were positional candidate genes

CaseGenotypingMethod: homozygosity mapping (50K SNP array), candidate gene sequencing

Variant: c.940del (p.Tyr314fs) "c.940delT"

ClinVarID: or CAID: CA351489

gnomAD: This frameshift variant, Tyr314fs, is absent from gnomAD v4.0.0 and occurs in exon 6/6. Downscoring since NMD is not expected to occur.

AddCaseInfo: first-cousin parents

PreviouslyPublished: 17461801

VariantEvidence: Functional in Xenopus oocytes demonstrated transport activity that was approximately one-fourth that of WT SLC29A3. Studies in NIH 3T3 fibroblasts showed mistrafficking of the mutant protein to the ER or Gogli apparatus (Kang et al. 2010; PMID: 20595384).

Mouse models should potentially be downgraded given the significant difference in telomere biology

Case# II-4, Female, 14, Ireland

CasePresentingHPOs HP:0002506, HP:0002497, HP:0002061, HP:0011448, HP:0001347

CasePreviousTesting Initial genetic testing (with patient consent) included a screening panel for HSP, as well as SCA 1, 2, 3 and 6, all of which were negative.

CaseMethod1 WES

Variant NM_005186.3:c.1534C>T(p.Arg512Cys)

CAID CA6093457

gnomAD 0.000008977

Case# Patient 5, Caucasian, Female, age 61

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10580G>A (p.Arg3527Gln)

ClinVar 17890

gnomAD 0.0005791 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P5=240, PMID: 3477815- reduced LDLR affinity

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

Case# Travaglini 1, Male, 16 report, Italian

CasePresentingHPOs HP:0006895, HP:0040083, HP:0001347, HP:0003487

CasePreviousTesting Sanger of SPG4 and 89 other known/candid genes by Nextera Custom Enrichment panel

CaseMethod1 Sanger Sequencing

CaseGenotypingMethod CAPN1 variants found in same panel screen

Variant NM_005186.3:c.221G>A (p.G74D), NM_005186.3:c.911C>T(p.T304M), NM_005186.3:c.1418G>T (p.R473L)

CAID CA6092976, CA6093221, CA6093432

gnomAD 0.0006904 , 0.0003415, 0.00003952

CaseAddInfo nonconsanguineous family

Cultured patient fibroblasts showed disappearance of filamentous mitochondria in favor of fragmented and punctuated mitochondria and a 20% decrease of mitochondrial content in fibroblasts.

Case3: Male, 41 yrs report

CasePresentingHPOs: HP:0012432, HP:0003738, HP:0003236, HP:0003273, HP:0003044, HP:0012785, HP:0006466, HP:0005997, HP:0003798, HP:0100295, HP:0031237, HP:0003201, HP:0012548 (Chronic fatigue, Exercise-induced myalgia, Elevated serum creatine phosphokinase, Hip contracture, Shoulder flexion contracture, Flexion contracture of finger, Ankle contracture, Neck flexion contracture, Nemaline bodies, Muscle fiber atrophy, Internally nucleated skeletal muscle fibers, Rhabdomyolysis, Skeletal muscle fatty infiltration)

HPOsFreeText: Jaw contractures, Core-like regions

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo via parental testing

CasePreviousTesting: ACTA1 and TPM3 were sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case2: Male, 14 yrs report

CasePresentingHPOs: HP:0002355, HP:0002527, HP:0000023, HP:0001763, HP:0002942, HP:0001276, HP:0006466, HP:0003089 (Difficulty walking, Falls, Inguinal hernia, Pes planus, Thoracic kyphosis, Hypertonia, Ankle contracture, hamstring contracture)

HPOsFreeText: In-toe gait, Tendo-Achilles release performed

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Son of Case 1, Variant is de novo in mother

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case5: Female, 50 yrs report

CasePresentingHPOs: HP:0002355, HP:0100753, HP:0003089, HP:0003798, HP:0031237, HP:0031318 (Difficulty walking, Schizophrenia, Hamstring contracture, Nemaline bodies, Internally nucleated skeletal muscle fibers, Myofiber disarray)

HPOsFreeText: Jaw contractures, Pectoral contractures, Ankle dorsiflexor contractures, Quad contractures, Increased oxidative staining

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Daughter of Case 4, Sibling of Case 6

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case8: Female, 65 yrs report

CasePresentingHPOs: HP:0001263, HP:0030051, HP:0003326, HP:0003731, HP:0002540, HP:0003236, HP:0006466, HP:0005830, HP:0012785, HP:0009600, HP:0003798, HP:0031237, HP:0003555, HP:0001761 (Delayed milestones, Tip-toe gait, Myalgia, Quadriceps weakness, Non-ambulatory, Elevated serum creatine phosphokinase, Ankle contracture, Toe contractures, Flexion contracture of finger, Contracture of thumb, Nemaline bodies, Internally nucleated skeletal muscle fibers, Muscle fiber splitting, Pes cavus)

HPOsFreeText: Tendo-achilles release performed, NCPAP from 54 yrs, Jaw contractures, Nuclei clumps, Fiber type grouping, Required non-invasive nocturnal ventilatory support at age 54 years

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: ACTA1 was sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case1: Female, 45 yrs report

CasePresentingHPOs: HP:0008994, HP:0002015, HP:0003236, HP:0003273, HP:0031237, HP:0003555, HP:0100295, HP:0012548 (Proximal muscle weakness in lower limbs, Dysphagia, Elevated serum creatine phosphokinase, Hip contracture, Internally nucleated skeletal muscle fibers, Fiber splitting, Muscle fiber atrophy, Skeletal muscle fatty infiltration)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband of Family 1, Mother of Case 2, Variant is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case#: II.4 - male, 23, European descent II.5 - male, 28, European descent CasePresentingHPOs: Both patients II.4 and II.5 - HP:0003233 (low HDL cholesterol), HP:0012153 (hypotriglyceridemia), HP:0003563(decreased LDL cholesterol)

CaseMethod1: Exome CaseMethod2: Sanger

Variant: NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)

ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

VariantEvidence: 12 other individuals from the Dallas Heart Study with ANGPTL3 frameshift mutations with phenotypes in Supplementary doc (PMID 19075393), additive dosage model with 2 mutations, 1 mutation and 0 (in supplementary table 5), “key enzymes in the metabolism of circulating triglycerides and HDL cholesterol, respectively, are elevated in Angptl3-knockout mice, suggesting that increased activity of these enzymes may explain the low levels of triglycerides and HDL cholesterol in humans with ANGPTL3 nonsense mutations” (PMIDs 17110602, 12097324, and 17681148)

Case4: Male, Spain, Post-birth onset

CasePresentingHPOs: HP:0003798, HP:0001324, HP:0000297, HP:0003701, HP:0001252, HP:0001284, HP:0002307, HP:0000218, HP:0001382 (Nemaline bodies, Muscle weakness, Facial hypotonia, Proximal muscle weakness, Muscular hypotonia, Areflexia, Drooling, High palate, Joint hypermobility)

HPOsFreeText: Cephalic support, Sedestation

CaseNotHPOs: HP:0000602, HP:0001249, HP:0001627, HP:0002093, HP:0002307, HP:0003722, HP:0002460, HP:0001283, HP:0002650, HP:0002540, HP:0006466, HP:0011471 (Ophthalmoplegia, Intellectual disability, cardiac abnormality, Ankle contracture, Drooling, Neck flexor weakness, Distal muscle weakness, Bulbar palsy, Respiratory insufficiency, Inability to walk, Scoliosis, PEG-fed in infancy)

NotHPOsFreeText: Bimodal communication, Wheelchair dependence, Mechanic ventilation

CaseAddInfo: Typical variant, Paternity/maternity was confirmed, cDNA analysis confirmed that Variant 1 results in a splice-site donor mutation which skips exon 24 which was confirmed by Sanger sequencing and leads to this deletion: p.His738_Asp770del (c.2212_2310del)

CasePreviousTesting: N/A

CaseGenotypingMethod: A research panel with 751 genes relating to neurological disorders, including the coding and intronic flanking regions of ACTA1, CFL2, KBTBD13, NEB, TNNT1, TNNT3, TPM2 and TPM3, was used to locate any variants in the proband. These variants were then prioritized and confirmed by Sanger sequencing in the probands and their relatives.

Variant1: NM_001164507.1:c.2310+5G>A (p.=)

CAID: CA913203562 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203562

gnomAD: Not in gnomAD

Variant2: NM_001164507.1:c.17779_17780del (p.Tyr5927Hisfs*17)

CAID: CA913203561 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203561

gnomAD: Not in gnomAD

Case1: Male, Spain, Birth onset

CasePresentingHPOs: HP:0003722, HP:0001324, HP:0000297, HP:0003701, HP:0001252, HP:0001284, HP:0001283, HP:0002540, HP:0002307, HP:0000218, HP:0011471 (Nemaline bodies, Muscle weakness, Facial hypotonia, Proximal muscle weakness, Muscular hypotonia, Areflexia, Bulbar palsy, Inability to walk, Drooling, High palate, PEG-fed in infancy)

HPOsFreeText: Bimodal communication, Wheelchair dependence, Cephalic support, Sedestation

CaseNotHPOs: HP:0002460, HP:0000602, HP:0001249, HP:0001627, HP:0002093, HP:0002650, HP:0006466, HP:0001382, HP:0003798 (Neck flexor weakness, Distal muscle weakness, Ophthalmoplegia, Intellectual disability, cardiac abnormality, Respiratory insufficiency, Scoliosis, Ankle contracture, Joint hypermobility)

NotHPOsFreeText: Mechanic ventilation

CaseAddInfo: Intermediate variant, Paternity/ maternity was confirmed

CasePreviousTesting: N/A

CaseGenotypingMethod: A research panel with 751 genes relating to neurological disorders, including the coding and intronic flanking regions of ACTA1, CFL2, KBTBD13, NEB, TNNT1, TNNT3, TPM2 and TPM3, was used to locate any variants in the proband. These variants were then prioritized and confirmed by Sanger sequencing in the probands and their relatives.

Variant1: NM_001164507.1:c.17779_17780del (p.Tyr5927Hisfs*17)

CAID: CA913203561 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203561

gnomAD: Not in gnomAD

Variant2: NM_001164507.1:c.11086A>C (p.Thr3696Pro)

CAID: CA348785269 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.11086A%3EC

gnomAD: Not in gnomAD

Transfection into COS-7 cells showed that this variant has 1.2% IDUA activity compared to WT

PMID: 29801986

Gene: CPS1

Disease: Carbamoyl phosphate dehydrogenase deficiency

MONDO:0009376

InheritancePattern: AR

CaseFSIP2_1 male, 44yo report, Tunisian

CasePresentingHPOs HP:0003251, HP:0012207, HP:0012868

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 2.5mL, sperm concentration: 6.7 million/mL, total motility: 1h, vitality: 47%, normal spermatozoa: 0%, absent flagella: 2%, short flagella: 32%, coiled flagella: 26%, flagella of irregular caliber: 57%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.910del (p.Gln304Lysfs)

ClinVar 586972

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

CaseF1:III-1: Female, Italy

CasePresentingHPOs: HP:0001634 (Mitral valve prolapse)

CaseAddInfo: Proband for F1

CaseF4:II-1: Male, Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F4

CaseF6:II-1: Male, Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F6

Case: Mohlo-Pessach Patient 2, male, 20yo at report, Arab

CasePresentingHPOs: HP:0000365, HP:0000953, HP:0000998, HP:0004322, HP:0001999, HP:0000494, HP:0003196, HP:0000463, HP:0001084, HP:0001433, HP:0100490, HP:0001935, HP:0003565, HP:0011227, HP:0002716, HP:0100727

CasePresentingHPOsFreeText: Cutaneous induration and hyperpigmentation of the thighs appeared at 8yo, spread to genitals, back, and lower limbs. Retrognathism. Scrotal masses. Fixed flexion contractures of the proximal interphalangeal joints of the right fourth and fifth fingers and the left fifth finger. Skin biopsy included dermal infiltrate consisting of lymphocytes, plasma cells and CD68+ histiocytes, and dermal and subcutaneous fibrosis.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: SLC29A3 exons and splice junctions were PCR-amplified using intronic primers. PCR products were purified and sequenced on ABI 3700 capillary sequencer.

Variant: c.1088G>A (p.Arg363Gln)

ClinVarID: or CAID: CA129562

gnomAD: This missense variant, Arg363Gln, is present in gnomAD v4.0.0 with a MAF=0.0002666 (16/60010 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous parents

PreviouslyPublished: n/a

VariantEvidence: n/a

PMID: 32360764

Variant NM_000280.5:c.333C>A(p.Val111=)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Notes Proband with confirmed aniridia and confirmed de novo appearance of the variant, summary in table 1, proband information in the "splice variant" section. It is noted however that the authors do not include the parental genotype or phenotype data.

Clinical Lab The Wessex Regional Genetics Laboratory has been contacted for variants c.333C>A and c.1183G>C, there is no additional information than what is in the table and if familial or de novo is claimed it is because parental samples were collected and tested negative for the variant in the published proband

Cell transfection assays showed marked exon 2 skipping in these assays, but also yielded a large fraction of normal transcripts.

c.51+3A>G mutation cosegregates with low C1 inhibitor protein levels in one family. alternative splicing of exon 3, found in peripheral blood cell mRNA but not in the liver or in hepatoma cell lines and we show that, in cultured monocytes of a patient carrying the c.51+3A>G mutation, this alternative splicing is shifted from exon 3 exclusion to skipping of both exons 2 and 3

Variants: c.51+3A>G; c.51+5G>A

CAIDs: CA2579981804; error in CAR-unable to register

MiltingF1

FamilyNotHPOs HP:0100660, HP:0004756, HP:0001645, HP:0031317

CountryOrigin Germany

Ethnicity Danish

Family#PreviousTesting: whole genome Family#Method1 PCR

Family#GenotypingMethod Liquid Chromatography screening

Affected 8

Unaffected 6

Segregations 7

eLOD 2.1

ProbandLabel Milting3:1 female

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

Case: TTD218UT

Demographics: Female, 1.5 years at diagnosis. Moroccan origin.

CasePresentingHPOs: HP:0004779, HP:0045055, HP:0008064, HP:0000252, HP:0001263, HP:0004322, HP:0001935, HP:0004840, HP:0040082, HP:0100025

Individual showed recurrent aggravation of hair-loss by tufted breakage at the scalp boundary immediately following episodes of infection-induced fever, and upon long-term exposure to the heat of the sun, she appears to have increased hair-loss. She had an IQ of 54 (at 7 years) and limited physical endurance.

CaseNOTHPOs: Progressive deterioration at 8 years

CasePreviousTesting: None

CaseGenotypingMethod: Whole genome sequencing, confirmed by Sanger sequencing.

Variant: NM_002095.5(GTF2E2):c.C559T [p.Asp187Tyr]

ClinVar ID: 225841

Pathogenic, non-LOF variant gnomAD: hypomorphic, homozygous missense. Not in gnomAD.

AddCaseInfo: The parents of this individual were consanguineous and were heterozygous for the mutation. Of 3 siblings, two (a brother and a sister) were found to be heterozygous carriers, while one was found to have the homozygous wild type alleles (a sister).

VariantEvidence: The variant has been previously reported by Kauschal et al (26996949) in a 16-yr old Moroccan girl. The identification of this variant in four individuals of Moroccan origin suggests the possibility of a founder mutation. Since the variant has been already scored, this proband is not being scored.

Case: Family 11 GC21390 Proband II:1, 49yo at onset (incidental finding), 56yo at report

CasePresentingHPOs:

CasePresentingHPOsFreeText: Prolonged dark adaptation, peripheral visual field loss, BCVA= 6/9, 6/5, retinitis pigmentosa, hypertension, plasma coQ10 level=582.28nmol/L (Reference range: 227- 1432 nmol/L)

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: negative IRD gene panel analysis

CaseGenotypingMethod: genome sequencing, direct Sanger

Variant: c.933delC p.(Tyr311); c.682-7 T > G p.(Gln230); p.(Leu193Phefs*27)

ClinVarID: or CAID: CA6828694; CA6828747

gnomAD: This nonsense variant, Tyr311Ter in exon 7/7, is present in gnomAD v4.1.0 with a MAF=0.00002627 (31/1179996 alleles) in the European NF population with 0 homozygotes. The score has been reduced since NMD is not expected to occur.

This non-canonical splice site variant, c.682-7T>G, is present in gnomAD v4.1.0 with a MAF=0.001031 (66/64040 alleles) in the European Finnish population with 0 homozygotes.

AddCaseInfo: only family member noted to be affected, mother was unaffected and heterozygous for tyr311ter but father is deceased and not genotyped

PreviouslyPublished: n/a

VariantEvidence: RT-PCR of patient blood derived mRNA using oligonucleotide primers targeting COQ5 (Supplementary Table 6) followed by agarose gel electrophoresis showed definite altered transcript length and mis-splicing for the COQ5 c.682-7 T > G variant. ONT sequencing of the full COQ5 transcript from whole blood of individual family 11, II:1 showed skipping of exon 5 to be the predominant effect of the c.682-7 T > G variant leading to early termination and probable nonsense-mediated decay (p.(Gln230)) (Fig. ​(Fig.4).4). In addition, exon 4–5 skipping was identified in a low proportion of reads (3%) leading to a reading-frame shift and early termination (p.(Leu193Phefs27)).

Case: Family 12 Proband, 5yo at onset, 38yo at report

CasePresentingHPOs:

CasePresentingHPOsFreeText: Muscle weakness (hyposthenia), followed by vision problems in the dark (14), BCVA=6/18, 6/7.5, retinitis pigmentosa, nystagmus, infantile appearance, hypertelorism, undeveloped fertile function, constricted visual field

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: negative IRD gene panel analysis

CaseGenotypingMethod: "genome-wide analysis" -exome or genome sequencing

Variant: c.367 C > T p.(Arg123Trp); c.682-7 T > G p.(Gln230); p.(Leu193Phefs27)

ClinVarID: or CAID: CA6828832; CA6828747

gnomAD: This non-canonical splice site variant, c.682-7T>G, is present in gnomAD v4.1.0 with a MAF=0.001031 (66/64040 alleles) in the European Finnish population with 0 homozygotes.

This missense variant, p.Arg123Trp, is present in gnomAD v4.1.0 with a MAF=0.00002665 (2/75052 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: only family member noted to be affected, others do not have genotype information available

PreviouslyPublished: n/a

VariantEvidence:

Case: Individual 3, male, 7.5 yo

CasePresentingHPOs: HP:0000750, HP:0001263, HP:0001290, HP:0002360, HP:0007018, HP:0000736, HP:0004673, HP:0000735, HP:0000629, HP:0000316, HP:0004209, HP:0001212, HP:0001382,

CasePResentingHPOText: Subject began walking at 18 months. Testing for autism gave the following results: WPPSI-III-NL: TIQ 98, VIQ 106, PIQ 96.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0000202, HP:0000504,

CasePreviousTesting: Metabolic screening, SNP-array, and Fragile X (FMR1) testing were normal

CaseGenotypingMethod: Trio-WES. Individual is noted as being mosaic (60%) for the FBXO11 mutation. Testing also identified a VUS in TP73 (NM_0054 27.3):chr1: g.3644250 G>A, c.901G>A; p.(Asp301Asn). Not noted as de novo, so assume inherited and parents were not noted as having behavioral abnormalities or intellectual disability.

Variant: hg19:chr2: g.4806611 8=/T>C, c.467=/A> G p.(Gln156Arg) or NM_001190274.1:c.467A>G

CA ID: CA346813225

de novo Trio-WES performed so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: Individual is noted as being mosaic (60%) for the FBXO11 mutation. Gln156 is located just N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the Q156R mutation on FBXO11 function.

Case: Individual 9, male, AOR= 3 years 10 months

CasePresentingHPOs:  HP:0004322, HP:0004325, HP:0000252, HP:0001263, HP:0001611, HP:0001256, HP:0001290, HP:0002360, HP:0000736, HP:0030213, HP:0001090, HP:0002553, HP:0000527, HP:0000494, HP:0000316, HP:0000426, HP:0000455, HP:0000322, HP:0000219, HP:0000307, HP:0000179, HP:0000400, HP:0011271, HP:0200055, HP:0009836, HP:0001212, HP:0001852, HP:0000565, HP:0000915

CasePresentingHPOText: Began walking at 13 months, first words at 23 months. Intelligence testing should an IQ of 75-88 but noted as uneven profile.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0000202

CasePreviousTesting: Affymetrix Cytoscan Array screening was normal

CaseGenotypingMethod: Individual WES (Illumina HiSeq 2500), filtering against known and candidate genes from SysID (by Konchinke et al., 2016 PMID: 26748517). Sanger sequencing for confirmation and to test the parents and show absence of the variant. The sample identity was also confirmed.

Variant: hg19:chr2: g.4806682 1_4806682 2del, c.319_320 del, p.(Leu107Alafs45) OR* NM_001190274.1:c.319_320del

CA ID: CA658820927

de novo

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The Leu107Alafs*45 mutation causes a frameshift mutation and premature stop codon. The mutation start in exon 2 and thus removes the F-BOX, all three CASH domains and the zinc-finger UBR region, thus it should act as a loss of function variation. No functional assays or variant evidence was provided.

PMID: 24035930

Gene: GALNS

Disease: Mucopolysaccharidosis type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

GroupPresentingHPOs: only shared phenotype was reduced GALNS activity in leukocytes

GroupGenotypingMethod: Sanger seq of amplified exons

NumberMales: 15

NumberFemales: 6

NumberFamilies: 19

CountryOrigin: China

AgeRange: 1yo to 7.8yo

TotalNumber: 21

FamilyInfo:19 families, siblings P1 and P2, P3 and P4, parents were studied for segregation info

VariantCount: 15

PMID: 24172204

GeneName: SLC29A3

HGNC: HGNC:23096

Disease: H syndrome

MonDO ID: MONDO:0011273

Inheritance: AR

great review of cases to curate

Case: Patient 1, female, AOR 2 years, Turkish

CasePresentingHPOs: HP:0001561, HP:0003265, HP:0001270, HP:0000924, HP:0000253, HP:0002007, HP:0000520, HP:0005280, HP:0003196, HP:0000463, HP:0005306, HP:0000212, HP:0000347, HP:0005619, HP:0002938, HP:0000960, HP:0009826, HP:0001156, HP:0004060, HP:0100543, HP:0008936, HP:0007340, HP:0001265, HP:0005193, HP:0002063, HP:0002240, HP:0001407, HP:0100625, HP:0004565, HP:0005619, HP:0002867, HP:0100865, HP:0003016, HP:0003416, HP:0002176, HP:0006532, HP:0000670, HP:0004315, HP:0002850,

CaseNOTHPOs: HP:0000365, HP:0000504

CasePreviousTesting: Lab examines including urine organic acid analysis (urine glycosaminoglycan/ GAG and lysosomal enzymes), tandem mass screening, chromosome analysis, electroencephalogram were unremarkable. Negative for mutations in SLC35D1 (Schneckenbecken dysplasia MIM 269250), and INPPL1 (opsismodysplasia; MIM 258480) .

CaseGenotypingMethod: WES

Variant: NM_001440.3: c.953C>T(p.P318L)

CA ID: CA370858101

Homozygous

gnomAD: no homozygotes, only 2 hets in Euro-ND populatin CA370858101

AddCaseInfo: Parents were also tested by WES and were both found to be carriers of the mutation.

VariantEvidence: WEstern blot analysis of EXTL3 from patinet 1 cells shows expression of hte P318L variant (Figure 1B), indicating the protein is still produced. However, a glycosyltransferase assay using the wildtype EXTL3 and th eP318L variant showed reduced enzyme activity in the P318L variant compared to wildtype, and simiar levels of activity as untransfected/ mock controls. This indicates the P318L mutation acts as a loss of protein function of the enzyme activity.

***Note, this patient shows overlap of several homozygous regions and alterations with PAtient 1. Althgouh they state they are unrelated, it seems evident that they may be distantly related, the Parents of Patient 2 are consanguineous and the Turkish population. Patietn 1 is Turkish, and the parents are not marked as being consanguineous.

Case: Patient 2, female, Turkish

CasePresentingHPOs: 

CaseNOTHPOs:

CasePreviousTesting: Negative for mutations in SLC35D1 (Schneckenbecken dysplasia MIM 269250), and INPPL1 (opsismodysplasia; MIM 258480).

CaseGenotypingMethod: WES

Variant: NM_001440.3: c.953C>T(p.P318L)

CA ID: CA370858101

Homozygous

gnomAD: no homozygotes, only 2 hets in Euro-ND populatin CA370858101

AddCaseInfo:

VariantEvidence: WEstern blot analysis of EXTL3 from patinet 1 cells shows expression of hte P318L variant (Figure 1B), indicating the protein is still produced. However, a glycosyltransferase assay using the wildtype EXTL3 and th eP318L variant showed reduced enzyme activity in the P318L variant compared to wildtype, and simiar levels of activity as untransfected/ mock controls. This indicates the P318L mutation acts as a loss of protein function of the enzyme activity.

Case# Baskin RW, Female, 31

CasePresentingHPOs HP:0004756, HP:0011841, HP:0002013

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# Baskin TS, Male, 16

CasePresentingHPOs HP:0006956, HP:0100749, HP:0001962, HP:0004756

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.829A>T (p.Thr277Ser)

ClinVar 165456

gnomAD 0.006432 link

Case# Baskin EK, Female, 47

CasePresentingHPOs HP:0010872, HP:0100660

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# Baskin YH, Male, 12

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.1111T>C (p.Tyr371His)

ClinVar 46140

gnomAD 0.01076 link

This variant was found in homozygosity in patient #184 from Uzbekistan. The maximum point total for homozygosity has already been reached for this variant.

This case has been added to the VCI and assessed already.

PreviouslyPublished: PMID: 18158317

This family has been added to the VCI and assessed separately.

PreviouslyPublished: PMID:18065439

Case#: Family 1- II:2, female, 49 years

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0001397, HP:0000819 (liver steatosis, diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 20 mg/dl, HDL-C 120 mg/dl, TG 18 mg/dl (see additional values in Table 1). ApoB100 <10 mg/dl (normal range 49-88) (Supplemental data) Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter), heterozygous

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

Family#: Family 1

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

Family#Method1: Next generation sequencing

Family#GenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family 1- II:2

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter)

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

FamilyAddInfo: Pedigree Fig 1. The two family members who did not carry the variant presented normal LDL-C levels.

Case: Family III-I:2

CaseHPOs: HP:0003563, (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: Heterozygous (Chr2:21,230,941; c.8799 G > T; APOBp.Cys2933*) TC 145 mg/dl, LDL-C 55 mg/dl, HDL-C 81 mg/dl, TG 45 mg/dl (see additional values in Table 1). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

AddInfo: Mother of Family III-II:2. Other daughter (II-1) also has low LDL-C, but no genetic testing results available.

Case: Family IV-III:2, 19 year old female

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819, HP:0001397 (Diabetes, liver steatosis)

CasePreviousTesting: TC 124 mg/dl, LDL-C 49 mg/dl, HDL-C 62 mg/dl, TG 65 mg/dl (see additional values in Table 1)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Daughter of Family IV-II:1

Case16 Female, Finland

CasePresentingHPOs HP:0003826, HP:0000202, HP:0000347, HP:0001162, HP:0001829, HP:0010066, HP:0000157, HP:0002101, HP:0000238, HP:0007370, HP:0010664, HP:0007260

(Stillbirth, Oral cleft, Micrognathia, Postaxial hand polydactyly, Foot polydactly, Duplicated hallux, Tongue abnormality, Defective lung lobation, Hydrocephalus, Callosal agenesis, Fused thalami, Type II lissencephaly)

HPOsFreeText Crown-heel body length 47cm, body weight 2520g, abnormal larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001627

(Congenital heart defect)

NotHPOsFreeText Hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo stillbirth, 34+0wk gestational age

CasePMIDs n/a

Case19 Male, Finland

CasePresentingHPOs HP:0000347, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Micrognathia, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel body length 49cm, body weight 3864g, brain weight 286g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, (Fig6:) markedly narrowed basis pontis with minute corticospinal tract and a larger tg above, dysplastic dentate nucleus with irregular neuronal strands and intermingled matrix-like small cells is seen in the cerebellar hilus

CaseNotHPOs HP:0001161, HP:0001829, HP:0001627, HP:0000157, HP:0007165

(Hand polydactyly, Foot polydactyly, Congenital heart defect, Tongue abnormality, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo died 1 minute after birth, 40+6wk gestational age

CasePMIDs n/a

Case#: 77 yo Female. French Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0033166, HP:0002090, HP:0200043, HP:0001875, HP:0032247, HP:0002205, HP:0006532,HP:0033005, HP:0040167, HP:0032215, HP:0003139, HP:0032155, HP:0002014, HP:0025085, HP:0001824, HP:0033431, HP:0032247, HP:0001875

CaseFreetextHPOs: Beginning at age 14 proband was hospitalized for pneumonia. Started at age 14- 62 developed pneumonia several times. Had immunoglobulin replacement therapy. Has finger and forehead warts. Multiple episodes of Bowen's Disease of cheek. Due to worsening CMV colitis she underwent total abdominal colectomy with end ileostomy at age 77.. CMV viral load was 8641 copies/mL. IgG 11.32(g/L), IgA .28(g/L), IgM.2 (g/L). IgA and IgM are below the reference range. Neutropenia occurred only while on (val)ganciclovir for CMV.

Person first evaluated at age 74. Colonic diseases No known consanguinity Proband was hospitalized as early as 14 years of age for pneumonia

CasePreviousTesting: Near-absence of ICOSL in plasma. Cell surface expression of ICOSL by flow cytometry-based evaluation of PBMC from whole blood revealed severely diminished levels on CD19+ B cells.

CaseMethod1: WES

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing (WES) was performed on whole blood DNA from the patient.

Variant: NM_015259.6:c.657C > G (p.N219K)

ClinVar: Not registered

CAID: CA321497070

gnomAD: 0.00006424

VariantEvidence: Proband was homozygous for the missense variant in ICOSLG, p.N219K. Similar to the previous paper this individual is also French Canadian. No known consanguinity. p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: Sibling of proband died of unknown cause or blood disorders

CasePMIDs:

Case#: 38 yo Male. Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0000246, HP:0032301, HP:0033004, HP:0002205, HP:0001875, HP:0004313, HP:0001888, HP:0000403, HP:0011108, HP:0012387, HP:0002090, HP:0200043, HP:0032215, HP:0032076, HP:0410028, HP:0100825, HP:0011107,

CasePresentingHPOsFreeText: Had recurrent sinusitis approximately once per year as a youth. Age 21 was hospitalized for pneumonia. Had genital warts at age 16. Absent cell-surface expression determines functional consequence of mutation on the T-cell. At age 35 IgG 10.9-17.6 (g/L), IgA .16-0.3(g/L), IgM 0.66-0.76 (g/L). IgA are below the reference range. At age 38 CD3+ T cells: 387; CD4+ T cells: 281 CD8+ T cells: 92 all below the reference range. Started intravenous immunoglobulin replacement which helped with his respiratory tract infection.

CaseNotHPOs HP:0002718, HP:0410295, HP:0410303, HP:0003453, HP:0031160, HP:0002863

CaseNotHPOsFreetext: Diphtheria

CasePreviousTesting: Flow cytometric analysis, using two different antibodies recognizing distinct epitopes of ICOSL, showed that its cell-surface expression was absent in P1. Confocal microscopy likewise demonstrated decreased cell-surface expression. Both showed that ICOSL was absent. Sequencing of CXCR4 identified no mutation.

CaseMethod1:WES

CaseMethod2:Sanger Sequencing

CaseGenotypingMethod: Whole-exome sequencing was performed on genomic DNA. Sanger Sequencing confirmed that he is homozygous for the variant.

Variant: NM_015259.6:c.657C>G(p.Asn219Lys)

ClinVar:

CAID: CA321497070

gnomAD: 0.00006424

​​VariantEvidence: No known direct consanguinity. RT PCR to compare the ICOSLG mRNA levels and it showed that there was not significant decay in the mRNA. We observed a similar phenomenon following transient transfection of HEK293T cells, which lack endogenous ICOSL, with either WT or p.N219K ICOSL protein. Western Blot analysis of whole cell lysates.p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: French ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. His parents were heterozygous and his healthy brother was homozygous for the WT allele

Case: Family 1 Moynihan Proband VII:7, female, Pakistani

CasePresentingHPOs: HP:0000407, HP:0004322, HP:0000135, HP:0100540, HP:0012385, HP:0002716, HP:0034920, HP:0034677, HP:0034391, HP:0030075, HP:0002862

CasePresentingHPOsFreeText: Eyelid swellings due to histiocytic deposits, diverse cytoplasmic inclusions in phagocytes and reticulum cells of bone marrow, Lymph node and eyelid show reactive features with small reactive lymphoid follicles and histiocytes within dilated sinuses resembling RDD. invasive ductal carcinoma grade 3 ER negative breast aged 43 years and carcinoma bladder (grade 3 papillary TCC) age 46 years

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of PRF1 and UNC5B

CaseGenotypingMethod: autozygosity mapping, genotyping (genome-wide linkage scan was performed using Affymetrix 250k SNP arrays), direct sequencing, PCR

Variant: c.300+1G>A homozygous

ClinVarID: or CAID: 130339/CA155238

gnomAD: This splice site variant in intron 2 is present in gnomAD v4.0.0 at a MAF=0.0002197 (20/91048 alleles) in the South Asian population with 0 homozygotes.

AddCaseInfo: brother is affected as well

PreviouslyPublished: PMID: 9545394

VariantEvidence: n/a

This variant is listed in table 1 and found on LitVar, but no case info is present and is likely mention of a previous publication

Case#: II-9, male, Asian, 38 yr, proband

DiseaseAssertion: HCM, LQT1

FamilyInfo: HCM passed on in family (figure 1)

CasePresentingHPOs: HP:0001279, HP:0001712, HP:0001639 (Syncope, Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

CaseHPOFreeText: physical examination; 12-lead ECG (SR, HR 57 bpm, P 80 ms, PR 164 ms, QRS 102 ms, QTc 423 ms); 2D echocardiographic study with S5-1 probe (MLVWT 14 mm, EF 62%, LVMI 94.27 g/m^2);

CaseNotHPOs: HP:0030148 (Heart murmurs)

CaseNotHPOFreeText: No inverted T wave: Normal QTc 440 ms

CasePreviousTesting: Additional Sanger sequencing for KCNQ1, MKLY2, TMEM70

CaseGenotypingMethod: Illumina-SolexaHiSeq 2000 sequencing from peripheral blood leococytes; bi-directional Sanger sequencing;

Variant: absent

ClinVar: absent

CAID: CA389036862 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389036862

gnomAD: absent

MultipleGeneVariants:

(1) KCNQ1 Variant:

Variant: NM_181798.1(KCNQ1):c.187C>T (p.Arg63Trp)

ClinVar: 53070 https://www.ncbi.nlm.nih.gov/clinvar/variation/53070/

CAID: n/a

gnomAD: absent

(2) MKLY2 Variant:

Variant: absent

ClinVar: absent

CAID: CA408526793 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA408526793

gnomAD: African 0.00006453 https://gnomad.broadinstitute.org/variant/20-30412153-A-G

(3) TMEM70 Variant:

Variant: NM_017866.6(TMEM70):c.440T>C (p.Ile147Thr)

ClinVar: 571761 https://www.ncbi.nlm.nih.gov/clinvar/variation/571761/

CAID: n/a

gnomAD: East Asian 0.0004893 https://gnomad.broadinstitute.org/variant/8-74893513-T-C

Case#: Carelli proband, 20yo, Italian, male, onset in first year of life

DiseaseAssertion: Behr syndrome

FamilyInfo: Parents are unrelated. c.1705+1G>T was also identified in the affected mother and in nine maternal relatives, three of which (III-10, III-14 and III-18) are clinically unaffected (pedigree in Fig. 1A). The 43-year-old proband’s mother (Fig. 1A, III-4 in the pedigree) had isolated optic atrophy, most evident on the temporal side (Fig. 1C), which segregated as a dominant trait in her family (Fig. 1A). The other affected individuals in this family all suffered a non-syndromic optic atrophy, which started in childhood and progressively worsened, but remained as an isolated symptom. c.1146A>G (p.I382M) is present in the clinically unaffected father and sister. There were no MRI structural or metabolic abnormalities in the father (III-3) and the mother (III-4) of the proband, except for a few focal hyperintensities in the cerebral white matter (Fig. 1K–L). Neither signs of optic neuropathy nor abnormal nerve conduction velocities were recorded upon neuro-ophthalmological exam of the proband’s father and the elder sister (III-3 and IV-3).

CasePresentingHPOs: HP:0006934, HP:0000648, HP:0002066, HP:0002359, HP:0007663, HP:0002064, HP:0002403, HP:0001776, HP:0002395, HP:0003487, HP:0007078, HP:0012898, HP:0012897, HP:0003535, HP:0003387, HP:0001272, HP:0000543, HP:0010871, HP:0002313, HP:0001310, HP:0002075, HP:0000639

CaseHPOFreeText: Bilateral optic atrophy. Motor difficulties and visual acuity worsened during childhood. Nerve conduction studies showed delayed sensory-motor velocities with reduced amplitudes of motor potentials. Somatosensory evoked potentials could not be recorded and motor evoked potentials showed absent potentials at lower limbs and delayed latency at upper limbs. Brainstem evoked potentials were delayed bilaterally. Repeated urine organic acid gas chromatography/mass spectrometry analysis revealed mild elevation of 3-methylglutaconic acid (8–20 μmol/mmol creatinine). Sural nerve biopsy demonstrated a marked reduction of the large-diameter myelinated axons (Fig. 1E–G). Teased fibre analysis disclosed regions of demyelination confined to the paranodal region, clustered in some axons, suggesting secondary demyelination. Ultrastructural examination confirmed the reduction of myelinated axons (not shown). Elevated serum lactic acid after standardized exercise. mild cerebellar atrophy and pathological accumulation of lactate in the CSF of lateral ventriculi. OCT examination of retinal nerve fibre layer (RNFL) thickness shows a diffuse reduction of thickness compatible with the severe optic atrophy. Positive Holmes rebound phenomenon. Vision was light perception with severe nystagmus in any direction of gaze. Compared to controls, mitochondrial ATP synthesis driven by complex I substrates (pyruvate and malate) was incrementally reduced in the mother’s fibroblasts bearing the c.1705+1G>T (III:4) mutation and in the proband’s fibroblasts (IV:4) carrying both mutations.

CaseNotHPOs:

CaseNotHPOFreeText: cognitive delay

GenotypingMethod: Direct sequencing of the entire coding regions of the OPA1 gene and the flanking intronic boundaries. Sequence analysis of the OPA3 gene excluded the presence of pathogenic mutations.

PreviouslyPublished:

Variant: c.1705+1G>T; c.1146A>G (p.I382M)

CAID: CA10576007

SupplementalData:

Case#: Case 12DG1568, female, Arab, 18mo

DiseaseAssertion: MPS Ih

FamilyInfo: Parents are a second-degree consanguineous couple with three other healthy children, and they had a son who died at 12 years of age and a cousin with a similar phenotype

CasePresentingHPOs: HP:0000280, HP:0100876, HP:0005280, HP:0000463, HP:0000256, HP:0001433

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: NM_000203.5(IDUA):c.613_617dup (p.Glu207fs) homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: genotype and phenotype in Table S1, S6

CaseVII-3: Male, 4 years report, Turkey

CasePresentingHPOs: HP:0004912, HP:0002540, HP:0002970 (Hypophosphatemic rickets, Inability to walk, Genu varum)

HPOsFreeText: -3.44 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted de novo and confirmed by parental testing, Proband is hemizygous for this mutation, Mutation is at splice donor site at Intron 2

CasePreviousTesting: Calcium levels (9.0 mg/dL), Decreased serum phosphate levels (3.1 mg/dL; reference 3.8-6.5), Elevated serum ALP (393 IU/L; reference 90-325), 25OHD3 levels (4.9 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (154.7 ng/L), TPR levels (58.7), Decreased TmP/GFR levels (1.82; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5(PHEX):c.187+1G>T

CinVar: 438537 https://www.ncbi.nlm.nih.gov/clinvar/variation/438537/

gnomAD: Not in gnomAD

CaseII:II-2: Female, 37 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970, (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.95 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted novel, Mother of II:II-3

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.1 mg/dL; reference 2.7-4.5), Normal serum ALP (111 IU/L; reference 41-120), 25OHD3 levels (10.5 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (73 ng/L), TPR levels (87), Decreased TmP/GFR levels (1.70; reference 2.2-3.6)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.979_983dup (p.His329Thrfs*4)

CAID: CA913187410 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187410

gnomAD: Not in gnomAD

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The proband reported has clinical features of neurofibromatosis, with a de novo donor splice site variant in NF1, as well as a 12-bp deletion in RAB39B, which the authors assert was responsible for the phenotypes of severe ID, behavioral problems and aggressiveness.

This variant was mentioned only because a novel variant was found at the same amino acid. No new case or experimental info.

CaseID D

VariantInPub IVS2+9G>A

MANE NM_001368894.2:c.-129+9G>A

Zygosity heterozygous

PhenotypesProband HP:0000568, HP:0000482, HP:0000518, HP:0000639, HP:0000647, HP:0000491

FamilyInfo No family or segregation information was included

SpliceFormVariant No RT-PCR or northern blot to confirm the intronic substitution lead to a splice variant

Case#: Ma_Proband

Demographics: east Asian? referenced in passing in discussion section

CasePresentingHPOs: HP:0003182, HP:0008812, HP:0002655, HP:0003621, HP:0000943, HP:0001498, HP:0003049, HP:0002857, HP:0004689,

CaseNotHPOs: HP:0008445, HP:0002751, HP:0000768, HP:0008445

CasePreviousTesting: Previous diagnosis Developmental dysplasia of the hip (DDH)

CaseMethod1: quantify urinary excretion of glycosaminoglycans using dimethylmethylene blue

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing

Variant HGVS: 1) NM_000512.5:c.1156C>T 2) NM_000512.5:c.1288C>G

ClinVar: 1) 700 2) N/A

CAID: 1) CA221040 2) CA397096290

gnomAD v2: 1) 16-88891261-G-A 2) N/A

VariantEvidence:

CaseAddInfo: Onset of symptoms age 8, compound het

CasePMIDs:

Family#PresentingHPOs: None

FamilyNotHPOs: Free of clinical phenotypes

CountryOrigin: China

Ethnicity: Chinese

Race: east Asian

Family#GenotypingMethod: Whole exome sequencing

Affected: None reported

Unaffected: mother and maternal grandmother carriers of same allele, father carrier for separate allele

Segregations: 2?

PublishedLOD: N/A

eLOD: too few segregations

AddSegregationInfo:

ProbandLabel: Ma_Proband

Variant: Maternal - NM_000512.5:c.1288C>G Paternal - NM_000512.5:c.1156C>T

ClinVar:

CAID:

gnomAD:

FamilyAddInfo: paternal allele is previously reported as pathogenic, maternal allele and has only been reported in one proband/family

FamilyPMIDs: 34557487

CA3281798

Variant 1: CA8401572 Variant 2: ClinVar ID: 66035

Case#: Consequence 23 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.2788G>A (p.Glu930Lys)

ClinVar: 42933 https://www.ncbi.nlm.nih.gov/clinvar/variation/42933/

CAID: n/a

gnomAD: absent

Case#: Consequence 20 Table 1 in Data Supplement (3 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.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

CAID: n/a

gnomAD: absent

Case#: Consequence 9 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.427C>T (p.Arg143Trp)

ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

CAID: n/a

gnomAD: 0.0001087 East Asian https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Case#: Consequence 30 Table 1 in Data Supplement (2 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.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

CAID: n/a

gnomAD: 0.00003097 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Case#: Consequence 11 Table 1 in Data Supplement (4 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.2779G>A (p.Glu927Lys)

ClinVar: 42932 https://www.ncbi.nlm.nih.gov/clinvar/variation/42932/

CAID: n/a

gnomAD: absent

Case: Lin Patient-female, south Asian, 5 years old at diagnosis

CasePresentingHPOs: HP:0001945, HP:0002013, HP:0002027, HP:0002240

CasePresentingHPOsFreeText: Mildly elevated liver function tests (AST 48 U/L, ALT 80 U/L) upon initial visit, transaminases (AST 133 U/L, ALT 112 U/L) remained elevated after a month. Non-fasting lipid levels were abnormal; repeat testing showed a fasting total cholesterol of 305 mg/dL and a triglyceride level of 142 mg/dL. Diffuse, microvesicular steatosis in the hepatic parenchyma. Portal tracts were expanded by foamy macrophages containing finely vacuolated material, which was periodic acid-Schiff positive and resistant to diastase digestion. Trichrome stain for collagen showed mild portal fibrosis with early delicate bridging fibrosis. Ultrastructurally, the cytoplasm had a moth-eaten appearance with the presence of lipid droplets and cholesterol crystals. Low acid lipase activity of 7.2 (no units provided) in the liver, with follow up low level of lysosomal acid lipase activity (0.008 nmol/punch/h) in blood.

CaseNOTHPOs: HP:0032316, HP:0001744, HP:0001404, HP:0001396, HP:0001408

CaseNOTHPOSFreeText:

CasePreviousTesting: Abdominal ultrasound. Infection workup was negative for cytomegalovirus, hepatitis A, Lyme disease, and malaria. She did have a positive Epstein-Barr virus IgM. CT of the abdomen and pelvis revealed an enlarged liver measuring up to 17cm in width and craniocaudal dimension. Test results for autoimmune hepatitis, WD, and alpha-1-antitrypsin deficiency were negative. Liver biopsy.

CaseGenotypingMethod: LAL gene sequence analysis was performed.

Variant: c.57_60delTGAG and c.894G>A

ClinVarID: or CAID: CA2573331826 and 203361

gnomAD: This proband has a four-nucleotide deletion, c.57_60delTGAG, in exon 2 of the LIPA gene. This variant is predicted to result in a premature translation stop downstream of the deletion (p.Glu20GlyfsTer6). The variant is not present in gnomAD. This proband is scored default points.

This proband has a synonymous variant, Gln298= on exon 8/10 in a cononical splice site, which causes an abnormal splicing that results in the in-frame skipping of exon 8. The variant is reported in 167/128942 European (non-Finnish) alleles at a frequency of 0.001295, with no homozygotes in gnomAD v2.1.1. This is the most frequent variant in CESD patients (present in 40-60% of patients reported in the literature), but it is not confirmed if this is due to a hotspot or a common ancestor. This proband is scored default points.

AddCaseInfo: Confirmed in trans

PreviouslyPublished: no

VariantEvidence: Predicted evidence only for deletion variant.

Expression analysis in patient fibroblasts found lysosomal acidic lipase (LAL) activity to be reduced to 6-12% of wild type (PMID: 22227072).

Case# Zhong 3:2, Male, China

CasePresentingHPOs (HP:0007675, HP:0000580, HP:0007994, HP:0100019) no?

CasePreviousTesting no

CaseMethod1 WES

CaseMethod2 Sanger

Variant NM_004698.2:c.1532A>C

CAID CA342282924

Case#: V:3

Demographics: Pakistani

CasePresentingHPOs: HP:0004322, HP:0000768, HP:0000470, HP:0002857, HP:0002650, HP:0002007, HP:0000431, HP:0010674, HP:0002515, HP:0009803, HP:0006119, HP:0001216, HP:0002986, HP:0003027, HP:0008802, HP:0030299, HP:0000926, HP:0004568

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Proband whole exome seq

Variant: NM_000512.5:c.697G>A

ClinVar: 1048200

CAID: CA8235027

gnomAD: 16-88902194-C-T

VariantEvidence: previous pub as pathogenic, and in silico data suggesting damage to catalytic domain

CaseAddInfo: Family was tested via single gene sanger seq., consanguineous parents both carriers, two affected siblings and three unaffected siblings

CasePMIDs:

Case# F3-II2, female, 1yo onset, French

CasePresentingHPOs HP:0006579, HP:0003155, HP:0001290, HP:0001397, HP:0001395, HP:0001263, HP:0001250, HP:0000718, HP:0000713, HP:0000709, HP:0012347, HP:0003124, HP:0003141, HP:0010837 (Neonatal Jaundice, Elevated alkaline phosphatase, Hypotonia, Steatosis, Hepatic fibrosis, Psychomotor delay, Seizures, Aggressive behavior, Agitation, Psychosis, Abnormal protein N-linked glycosylation, High cholesterol, Increased LDL cholesterol, Low ceruloplasmin)

HPOsFreeText Persistent moderate hypotonia, elevated AT, necrotic lesions on liver biopsy, steatosis and fibrosis(1yo), developed various behavioral issues by age 25

CaseNotHPOs n/a

CasePreviousTesting Metabolic work up: AST 1,780 U/l[normal range, 0–50 U/l], ALT 390 U/l[normal range, 0–50 U/l], and ALP 950 U/l [normal range, < 360 U/l], with increased bone fraction, ceruloplasmin 10 mg/dl[normal range, 15–60 mg/dl], type 2 CDG, abnormal N-glycosylation

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Sanger on proband targeting CCDC115.

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo unaffected brother

CasePMIDs 29759592

Case# F2-II1, male, Italian, 2yo diagnosis

CasePresentingHPOs HP:0006579, HP:0001433, HP:0010837, HP:0003124, HP:0003155, HP:0001263, HP:0001999, HP:0025321, HP:0012358, HP:0012347, HP:0003141 (Neonatal jaundice, Hepatosplenomegaly, Decreased ceruloplasmin, High cholesterol, Elevated alkaline phosphatase, Psychomotor delay, Dysmorphic facies, Liver copper accumulation, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Increased LDL cholesterol)

HPOsFreeText Elevated AT, ALT, cholesterol, jaundice, hepatosplenomegaly, low blood ceruloplasmin(neonate), Mild psychomotor disability, mild dysmorphic facies (2yo)

CaseNotHPOs n/a

CasePreviousTesting Failed to detect ATP7B on suspected Wilson disease. Metabolic work up: AST 422 U/l[normal range, 0–50 U/l], ALT 588 U/l[normal range, 0–50 U/l], ALP 976 U/l[normal range, < 360 U/l], type 2 CDG (2yo). Hepatic copper 125 μg/g dry weightnormal range, <40 μg/g, Altered ApoC3 pattern, type 2 CDG pattern

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger homozygosity in proband and heterozygosity in parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 26833332, 29759592

Family#PresentingHPOs HP:0001263, HP:0001433, HP:0003155, HP:0012358, HP:0012347, HP:0010837, HP:0001999 (Pyschomotor delay, Hepatosplenomegaly, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Decreased ceruloplasmin, Dysmorphic facies)

HPOsFreeText Elevated aminotranseferases, type 2 CDG

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic screen indicated elevated AT, bone derived ALP, and low ceruloplasmin.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES confirmed with Sanger homozygosity in siblings and heterozygosity in parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Affected 3

Unaffected 1

Segregations 3

PublishedLOD n/a

eLOD 1.32

AddSegregationInfo consanguinity

ProbandLabel F1-II1, female, 9yo report

Case1PresentingHPOs HP:0001252, HP:0003236 (Hypotonia, Elevated CK)

HPOsFreeText decreased coagulation factors

Case1PreviousTesting Metabolic work up: AST 130–158 U/l [normal range, 0–50 U/l], ALT 85–101 U/l [normal range, 0–50 U/l], and ALP 1,016 –1,193 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl]. No change in CD59 and CD55 expression in EBV-transformed lymphoblasts.

Case2 F1-II2, male, 5yo report

Case2PresentingHPOs HP:0003124, HP:0000276, HP:0000508, HP:0000592, HP:0000494, HP:0100295, HP:0001433 (Hypercholesterolemia, Long face, Ptosis, Blue sclera, Downslanting palpebral fissures, Muscle fiber atrophy, Hepatosplenomegaly)

HPOsFreeText Hepatosplenomegaly normalized with age, abnormal coagulation factors

Case2PreviousTesting Metabolic work up: AST 96–436 U/l [normal range, 0–50 U/l], ALT 140–995 U/l [normal range, 0–50 U/l], and ALP 1,070–1,577 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl], cholesterol 289 mg/dl [normal range, 120–200 mg/dl]

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

FamilyAddInfo A third ungenotyped sibling, F1-II4 did not have hypotonia, but otherwise presented similarly.

FamilyPMIDs 29759592

p.W31X in trans with p.P1380L

Case7: Female, 8 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0040083, HP:0003701, HP:0003323, HP:0008981, HP:0003458, HP:0030951 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Toe walking, Proximal muscle weakness, Progressive muscle weakness, Calf muscle hypertrophy, EMG: myopathic abnormalities, Skeletal muscle fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: HP:0100543 (Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this deletion, Mother is confirmed heterozygous

CasePreviousTesting: Peak CPK at 17,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

Variant: SGCG, 2-BP DEL, 793TG

ClinVar: 2007 https://www.ncbi.nlm.nih.gov/clinvar/variation/2007/

Also Reported As

Variant: NM_000231.2(SGCG):c.794_795GT[3] (p.Cys267fs)

ClinVar: 552513 https://www.ncbi.nlm.nih.gov/clinvar/variation/552513/

gnomAD: 0.00009923, https://gnomad.broadinstitute.org/variant/13-23898596-CTG-C

Case19: Male, 4 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0003458, HP:0008981, HP:0031322, HP:0032019, HP:0003701 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, EMG: myopathic abnormalities, Calf muscle hypertrophy, Myocardial lymphocytic infiltration, Muscle eosinophilia, Proximal muscle weakness)

HPOsFreeText: N/A

CaseNotHPOs: HP:0100543 (Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this deletion, Parents are confirmed heterozygous and consangeuinous

CasePreviousTesting: Peak CPK at 25,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

ClinVar: 2004 https://www.ncbi.nlm.nih.gov/clinvar/variation/2004/

Also Reported As

Variant: NM_000231.2(SGCG):c.525del (p.Phe175fs)

ClinVar: 189243 https://www.ncbi.nlm.nih.gov/clinvar/variation/189243/

gnomAD: 0.00009671, https://gnomad.broadinstitute.org/variant/13-23869568-CT-C

Case44: Female, 7 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0040083, HP:0003307, HP:0002527, HP:0003701, HP:0003323, HP:0009042, HP:0003458, HP:0100305, HP:0031542 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Toe walking, Hyperlordosis, Falls, Proximal muscle weakness, Progressive muscle weakness, Marked muscular hypertrophy, EMG: myopathic abnormalities, Ring fibers, Myelin-like whorls in vacuolated fibers)

HPOsFreeText: Wheelchair at 14 yrs

CaseNotHPOs: HP:0003115, HP:0100543 (Abnormal EKG, Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this duplication, Parents are confirmed heterozygous

CasePreviousTesting: Peak CPK at 20,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

Variant: NM_000231.2(SGCG):c.87dup (p.Gly30fs)

ClinVar: 2008 https://www.ncbi.nlm.nih.gov/clinvar/variation/2008/

gnomAD: 0.000008805, https://gnomad.broadinstitute.org/variant/13-23777919-A-AT

Case#: Newborn 5, female, 1.4 months, Taiwan

DiseaseAssertion: MPS1

FamilyInfo: proband is a twin with newborn 6, who has the same genotype

CasePresentingHPOs:

CaseHPOFreeText: IDUA enzyme activity in leukocytes= 0.81 (Ref. 4.87 ~ 54.70 μmol/g protein/h, with cut-off values of < 3.0), positive GAG tests (GAG tests including GAG quantification (DMB/Cre ratio), 2-dimensional electrophoresis, and quantitative analyses of GAG-derived disaccharides (DS and HS) by tandem mass spectrometry assay). DS=99.61 (ug/mL), HS=13.31 (ug/mL)-average DS and HS values of the normal population were 0.17 (±0.23) and 0.11 (±0.21), respectively

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.1037 T > G (p.L346R)  +  c.1091C > T (p.T364M)

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Case# IV-3, Female

CasePresentingHPOs HP:0007642

CasePreviousTesting Excluded mutations in other genes associated with CSNB

CaseMethod1 Sanger

Variant NM_002075.3(GNB3):c.200C>T (p.Ser67Phe)

ClinVar 242986

gnomAD 0.00004564(European(Non-Finnish)), 0.00002475(Overall)

VariantEvidence none

PMID 22830481

Disease Pulmonary fibrosis/ bone marrow failure syndrome

NonHumanModel: Vervet Monkeys (Chlorocebus pygerythrus)

GeneAlteration: PCR amplification and direct sequencing indicated that all of the vervet monkeys observed and one of the malbrouck monkeys had the TTR Ile122 allele, as opposed to the the other primates (including humans) that harbor the Met122 allele. Other than this variant, the sequence was identical to three other species of monkeys that did not demonstrate amyloidosis phenotypes including 95-98%, 93-94%, and 76-81% amino acid homologies to humans.

ModelPhenotype: HP:0031327, HP:0003216, HP:0011675, HP:0012664 (Transthyretin cardiac amyloidosis, Generalized amyloid deposition, Arrhythmia, Reduced ejection fraction)

ModelFreeText: Haphazardly arranged rigid amyloid fibrils in the heart, Increased cardiothoracic ratio, Increased plasma ANP concentrations

HumanPhenotype: HP:0001627, HP:0011034 (Abnormal heart morphology, Amyloidosis)

HumanFreeText: N/A

ModelEvidence: Aged vervet monkeys were investigated for a naturally-occuring spontaneous systemic amyloidosis and accompanying phenotypes. PCR amplification and direct sequencing of these monkeys and others showed that the vervet monkeys alone harbored the Ile122 allele, as opposed to the more common Val122 allele in other primates and humans. Histopathological investigations showed cardiac amyloidosis and rigid amyloid fibers in the heart, identical to that observed in aged humans with the allele in question. These deposits were also found in other systems such as the gastrointestinal tract, adipose tissue, lung, tongue, and vascular walls, also mirroring the multiple locations they were found in humans. Immunoblotting confirmed that amyloid proteins extracted from the cardiac specimens reacted with anti-TTR antibody. Other cardiac symptoms were observed that mirror those in humans, such as arrythmia and reduced ehection fraction. Real-time PCR showed that these monkeys and humans shared the majority of TTR expression patterns. Recombinant monkey TTRs showed a greater tendency to dissociate to monomers under the influence of urea-mediated denaturation stress than recombinant TTR of the cynomolgus monkey, which had the Val122 allele. ThT-binding assay also showed a higher number of amyloid fibers in the recombinant than the cynomolgus.

ModelVariant: NM_000371.4(TTR):c.424G>A (p.Val142Ile)

ClinVar: 13426, https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/

unable to annotate on PDF.

Case#: Case #20, Lombardia region of Italy

DiseaseAssertion: MPS1, intermediate

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Diagnosis of was based on the clinical features, excessive urinary glycosaminoglycan excretion, and reduced IDUA activity in fibroblasts and/or leukocytes. Intermediate phenotype is described as an onset of symptoms between 1 and 6 years, variable survival, and mental retardation being absent or mild but never before 3 years of age

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: direct sequencing

PreviouslyPublished: n/a

Variant: R628X homozygous

ClinVar: 550421

CAID: CA2802462

gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

SupplementalData: n/a

Case 2: male, diagnosed at 24 yrs, 38mm septal wall thickness, no mutations in HCM associated genes, no family history

HP:0002094, HP:0001681, HP:0001962, (dyspnea, angina pectoris, palpitations)

Variant: NM_020433.4(JPH2):c.421T>C (p.Tyr141His)

Clinvar ID: 30456

https://www.ncbi.nlm.nih.gov/clinvar/variation/30456/

ExAC Freq: 1.772e-05

Case 3: Female, diagnosed at 30 yrs, 18mm septal wall thickness, no mutations in HCM associated genes, no family history

HP:0002094, HP:0006689, (dyspnea, bacterial endocarditis)

Variant: NM_020433.4(JPH2):c.494C>T (p.Ser165Phe),

ClinVar ID: 30457

https://www.ncbi.nlm.nih.gov/clinvar/variation/30457/

not in ExAC