Variant: NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys)

CA013367

177753 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: c69683b9-ae34-4aea-98be-84cd024b37cf

Approved on: 2021-08-25

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.3133C>T
NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys)
ENST00000355349.4:c.3133C>T
ENST00000355349.3:c.3133C>T
NM_000257.3:c.3133C>T
NC_000014.9:g.23422292G>A
CM000676.2:g.23422292G>A
NC_000014.8:g.23891501G>A
CM000676.1:g.23891501G>A
NC_000014.7:g.22961341G>A
NG_007884.1:g.18370C>T

Uncertain Significance

• Met criteria codes: PS4_Moderate PP3 PM2

• Not Met criteria codes: PS2 PS1 PP1 PM6 PM1 PM5 BS4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID: 27532257; Michels 2017 PMID:28005231) and in an additional individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052). This variant was identified in 0.00152% (FAF 95% CI; 5/129168) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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_Moderate, PM2, PP3.

Met criteria codes

• PS4_Moderate: Variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID: 27532257; Michels 2017 PMID:28005231) and in 1 individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052).
• PP3: All tools and conservation, including REVEL support deleterious impact.
• PM2: Variant has been found in 0.00152% (FAF, 95% CI; 5/129168) of European chromosomes in gnomAD v.2.1.1

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Variant is outside the head domain where enrichment occurs.
• PM5: 2 additional variants at this codon: p.Arg1045Leu - also under evaluation by VCC, currently LP p.Arg1045His - 2* VUS in ClinVar, most recent is evaluation from 2019, only seen in a handful of cases per those evidence summaries; not evaluating further
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline