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_000257.4(MYH7):c.1013T>C (p.Val338Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA010070

42818 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: acab7662-647f-4066-9911-1a92a1460143

Approved on: 2021-03-22

Published on: 2021-08-25

HGVS expressions

NM_000257.4:c.1013T>C

NM_000257.4(MYH7):c.1013T>C (p.Val338Ala)

NC_000014.9:g.23429900A>G

CM000676.2:g.23429900A>G

NC_000014.8:g.23899109A>G

CM000676.1:g.23899109A>G

NC_000014.7:g.22968949A>G

NG_007884.1:g.10762T>C

ENST00000355349.4:c.1013T>C

ENST00000355349.3:c.1013T>C

NM_000257.3:c.1013T>C

Uncertain Significance

PS4_Supporting PM1 PM2

BS3 BS1 PS3 BA1 PP3

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.1013T>C (p.Val338Ala) variant in MYH7 has been identified in 4 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2; PM1

PS4_Supporting

This variant has been identified in 4 individuals with HCM (1 from Invitae, 1 from LMM - internal & Walsh 2017 PMID:27532257 & Homburger 2016 (SHaRe) PMID:27247418, 1 from GeneDx - internal & Homburger paper, 1 from Centenary Institute Sydney) No additional literature from Alamut search string in Google Scholar or HGMD. Internal data: 4 HCM (1 each from GeneDx, Invitae, LMM, and Centenary Institute Sydney), May have 1 segregation with Sydney, but specifics not known, so not counting. Per SHaRe data: seen in 3 pro bands, but only HCM known in 2 (1 tested at LMM and 1 tested at GeneDx; 1 unknown was tested at Seidman research lab, may have also been confirmed at LMM)

PM1

Variant is located within head region (aa 181-937)

PM2

Absent in gnomAD with ~30x coverage in genomes and ~80x coverage in exomes.

BS3

No evidence

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

No evidence

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

Computational tools are mixed. REVEL is just over the impact threshold. Variant is not conserved in cape golden mole and multiple birds and lower species.

Curation History

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