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.1358G>A (p.Arg453His)

CA010639

42838 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0be32c2f-1227-4089-b5fe-a3fd165b61d5

HGVS expressions

NM_000257.3:c.1358G>A

NM_000257.3(MYH7):c.1358G>A (p.Arg453His)

NM_000257.4:c.1358G>A

ENST00000355349.3:c.1358G>A

NC_000014.9:g.23429004C>T

CM000676.2:g.23429004C>T

NC_000014.8:g.23898213C>T

CM000676.1:g.23898213C>T

NC_000014.7:g.22968053C>T

NG_007884.1:g.11658G>A

Pathogenic

PS4 PP3 PM2 PM1 PM5 PM6

Evidence Links 6

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.1358G>A (p.Arg453His) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:20428263; PMID:15858117; PMID:20800588; PMID:21835320; PMID:22429680; Partners LMM ClinVar SCV000059369.5; Invitae ClinVar SCV000253816.4; SHaRe consortium, PMID: 30297972). This variant was been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:20428263). 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.1357C>T p.Arg453Cys; ClinVar Variation ID 14089). 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; PP3

PS4

>12 probands with HCM including ClinVar SCV000059369.5, ClinVar SCV000253816.4, SHaRe data

Variant identified in proband with HCM. Proband also carried Q882E variant in MYH7 PubMed:22429680

Variant identified in proband with HCM PubMed:21835320

Variant identified in 1 proband with HCM PubMed:15858117

Variant identified in proband with HCM PubMed:20800588

Variant identified in 1 proband with HCM. Proband also carried R403W variant inherited from father PubMed:20428263

PP3

Tools predict damaging

PM2

Absent from ExAC

PM1

Head domain (aa 181-937)

Head domain (aa 181-937) PubMed:27532257

PM5

NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys) - Variation ID 14089 - Pathogenic by Expert Panel

PM6

Variant occurred de novo in 1 proband with HCM

Variant occurred de novo in 1 proband with HCM PubMed:20428263

Approved on: 2016-12-15

Published on: 2018-11-16

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