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_000257.4(MYH7):c.707T>C (p.Val236Ala)

CA016653

43097 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b1bb9ce3-68be-445d-877e-426559812adb

Approved on: 2021-08-25

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.707T>C

NM_000257.4(MYH7):c.707T>C (p.Val236Ala)

NC_000014.9:g.23431610A>G

CM000676.2:g.23431610A>G

NC_000014.8:g.23900819A>G

CM000676.1:g.23900819A>G

NC_000014.7:g.22970659A>G

NG_007884.1:g.9052T>C

ENST00000355349.4:c.707T>C

ENST00000355349.3:c.707T>C

NM_000257.3:c.707T>C

Uncertain Significance

PS4_Supporting PM1 PM2

BS3 BS4 BS1 BP4 PS2 PS3 BA1 PP1 PP3 PM6 PM5

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.707T>C (p.Val236Ala) variant in MYH7 has been identified in 2 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers comm; LMM pers comm). This variant has also been observed in relatives with non-compaction cardiomyopathy, though this is considered insufficient to apply PP1. This variant was absent from large population studies (PM2; http://gnomad.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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to a lack of 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

Identified in 2 probands with HCM, one of whom had multiple VUS in other genes (Walsh 2017 PMID:27532257; GeneDx pers comm; LMM pers comm). This variant has also been observed in relatives with non-compaction cardiomyopathy, though this is considered insufficient to apply PP1.

PM1

Hotspot/est. functional domain (amino acids 181-937)

PM2

Absent from gnomAD with coverage of ~30x for genomes and ~100x for exomes, as well as ExAC, 1000 genomes and ESP

BS3

No functional evidence

BS4

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

BS1

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

BP4

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

PS2

No evidence

PS3

No functional evidence

BA1

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

PP1

LMM reports 1 HCM proband and an additional family member with LVNC with this variant. Not enough information to assess segregation and phenotypes in this family.

PP3

Mixed results for predictors, REVEL score is 0.616; conservation of valine is high in mammals (UCSC Genome Browser Multiz alignment).

PM6

No evidence

PM5

c.706G>A, p.Val236Ile - Evidence insufficient for P & 2* VUS in ClinVar 1/30616 in South Asian, 0.00327% Hotspot/est. functional domain (amino acids 181-937) Valine is well conserved in mammals (UCSC Genome Browser, multiz alignment) HGMD - PMID: 20474083, cannot find variant in paper, HGMD says it is in Supplementary Table 2 so 0 probands with variant.

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