Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp)

CA010360

14102 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d065fb29-95bd-49a8-951e-f52b10fac57c

Approved on: 2016-12-15

Published on: 2018-11-16

HGVS expressions

NM_000257.3:c.1207C>T

NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp)

NC_000014.9:g.23429279G>A

CM000676.2:g.23429279G>A

NC_000014.8:g.23898488G>A

CM000676.1:g.23898488G>A

NC_000014.7:g.22968328G>A

NG_007884.1:g.11383C>T

NM_000257.4:c.1207C>T

ENST00000355349.3:c.1207C>T

Pathogenic

PP1_Strong PM2 PM5 PM1 PS4 PP3

Evidence Links 4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1208G>A p.Arg403Gln - Variation ID 14087). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM1; PM2; PM5; PP3

PP1_Strong

>20 segregations

Variant segregated with disease in 12 family members PubMed:7662452

Variant segregated with disease in 11 family members PubMed:17612745

Variant segregated with disease in 5 affected family members PubMed:8254035

PM2

Absent from ExAC

PM5

c.1208G>A (p.Arg403Gln) - Variation ID 14087 - Pathogenic by ClinGen Expert Panel

PM1

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated PubMed:27532257

PS4

>20 probands with HCM reported

PP3

Tools suggest damaging

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