Evidence Repository
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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  • See Evidence submitted by expert panel for details.

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

CA013367

177753 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c69683b9-ae34-4aea-98be-84cd024b37cf

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 3
PS4_Moderate PP3 PM2
Not Met criteria codes 7
BS4 PS2 PS1 PP1 PM6 PM1 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
Approved on: 2021-08-25
Published on: 2021-10-01
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