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.2678C>T (p.Ala893Val)

CA012811

177763 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1db3f365-c635-4541-82da-6d48c06d14e6

Approved on: 2021-09-22

Published on: 2021-10-01

HGVS expressions

NM_000257.3:c.2678C>T

NM_000257.3(MYH7):c.2678C>T (p.Ala893Val)

ENST00000355349.4:c.2678C>T

ENST00000355349.3:c.2678C>T

NM_000257.4:c.2678C>T

NC_000014.9:g.23424770G>A

CM000676.2:g.23424770G>A

NC_000014.8:g.23893979G>A

CM000676.1:g.23893979G>A

NC_000014.7:g.22963819G>A

NG_007884.1:g.15892C>T

Uncertain Significance

PP1_Moderate PS4_Supporting PM2

PP3 BS3 BS4 BP4 PS3 PM5 PM1 PS1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with DCM (PS4_Supporting; Lakdawala 2012 PMID:22464770; Miller 2013 PMID:23054336; LMM pers. comm.). This variant segregated with disease in 5 affected individuals with DCM in 2 families (PP1_Moderate; Lakdawala 2012 PMID:22464770; LMM pers. comm.); however, in one of these families the variant was absent from a set of identical twins with mild LV dysfunction prior to testing at 4 months of age and additional clinical data was not available. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient and conflicting evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM5_Moderate, PM2.

PP1_Moderate

5 segregations total

PS4_Supporting

2 probands with DCM (Miller 2013 PMID:23054336, Lakdawala 2012 PMID:22464770, but were also LMM internal data) + 2 DCM from LMM 5 segregations with DCM from 2 families (one family from Miller had identical twins with borderline reduced EF that did not carry the variant; but insufficient to apply BS4). 1 proband with non-compaction cardiomyopathy No other literature via Google Scholar or HGMD Did not collect updated literature data

PM2

Absent from gnomAD (~30x coverage in genomes and ~70x in exomes)

PP3

Computational tools are mixed. PolyPhen2-HVAR predicts benign and Thr and Ser are both observed in several other mammals.

BS3

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

BS4

SCV000204046

BP4

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

PS3

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

PM5

NM_000257.4(MYH7):c.2677G>A (p.Ala893Thr) - 1* VUS NM_000257.4(MYH7):c.2677G>T (p.Ala893Ser) - 1* VUS NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) - Conflicting (also under evaluation, but will not be Pathogenic)

PM1

This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable.

PS1

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

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