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]

Variant: NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg)

Curation History

CA012013

14098 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 380d3ce8-4982-4df6-9bc5-6f4f7f75301c

Approved on: 2016-12-15

Published on: 2018-11-16

HGVS expressions

NM_000257.3:c.2221G>C

NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg)

NM_000257.4:c.2221G>C

ENST00000355349.3:c.2221G>C

NC_000014.9:g.23425760C>G

CM000676.2:g.23425760C>G

NC_000014.8:g.23894969C>G

CM000676.1:g.23894969C>G

NC_000014.7:g.22964809C>G

NG_007884.1:g.14902G>C

Pathogenic

PS4 PP3 PP1 PM2 PM1 PM5 PM6

Evidence Links 5

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). 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.2221G>T p.Gly741Trp - Variation ID 177665). 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; PM1; PM2; PM5; PM6; PP1; PP3

PS4

Variant identified in 12 probands (including SCV000059430.5 and SHaRe data)

Variant identified in 1 proband with HCM PubMed:15358028

Variant identified in 2 probands with HCM PubMed:20031618

Variant identified in 1 proband with HCM PubMed:8483915

Variant identified in proband with HCM PubMed:15563892

PP3

Tools predict damaging

PP1

3 segregations including ClinVar SCV000059430.5

Variant segregated with disease PubMed:8483915

PM2

Absent from ExAC

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

PM5

c.2221G>T (p.Gly741Trp) - Variation ID 177665 - Pathogenic by Expert Panel

PM6

Variant occurred de novo 1 proband

Variant occurred de novo in 1 proband with HCM PubMed:15563892

Curation History

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