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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Variant: NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys)

CA011642

177627 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ec7d0682-1bca-405e-8a16-1f2a5ffb8b69
Approved on: 2022-07-30
Published on: 2022-07-30

HGVS expressions

NM_000257.4:c.2080C>T
NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys)
NC_000014.9:g.23426046G>A
CM000676.2:g.23426046G>A
NC_000014.8:g.23895255G>A
CM000676.1:g.23895255G>A
NC_000014.7:g.22965095G>A
NG_007884.1:g.14616C>T
ENST00000355349.4:c.2080C>T
ENST00000355349.3:c.2080C>T
NM_000257.3:c.2080C>T

Likely Pathogenic

Met criteria codes 5
PS4_Moderate PP1 PP3 PM1 PM2
Not Met criteria codes 7
BS3 PS3 PS2 PS1 BP5 PM6 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.2080C>T (p.Arg694Cys) has been identified in at least 15 individuals with HCM, including 3 who also carried other potentially disease-causing variants (PS4_Moderate; Andersen 1999 PMID:10563488; Havndrup 2003 PMID:12566107; Andersen 2004 PMID:15114369; Van Driest 2004 PMID:15358028; Van Driest 2004 PMID:15519027; Olivotto 2008 PMID:18533079; Ho 2009 PMID:20031602; Jensen 2013 PMID:23197161; Witjas-Paalberends 2013 PMID:23674513; Coppini 2014 PMID:25524337; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry pers. comm; GeneDx pers. comm; Invitae pers. comm; LMM pers. comm). This variant segregated with disease in 4 affected relatives with HCM from 2 families (PP1; Andersen 2004 PMID:15114369; GeneDx pers. comm.). This variant was identified in 0.001% (FAF 95% CI; 4/113682) of European chromosomes by gnomAD v2.1.1 (PM2; https://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 suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2, PM1, PP3.
Met criteria codes
PS4_Moderate
This variant has been reported in at least 15 individuals with HCM, including 3 that also had truncating variants in MYBPC3 (PS4_Moderate; Andersen 1999 PMID:10563488; Havndrup 2003 PMID:12566107; Andersen 2004 PMID:15114369; Van Driest 2004 PMID:15358028; Van Driest 2004 PMID:15519027; Olivotto 2008 PMID:18533079; Ho 2009 PMID:20031602; Jensen 2013 PMID:23197161; Witjas-Paalberends 2013 PMID:23674513; Coppini 2014 PMID:25524337; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry pers. comm; GeneDx pers. comm; Invitae pers. comm; LMM pers. comm).
PP1
This variant segregates with HCM in 4 affected relatives from 2 families (PP1; Andersen 2004 PMID:15114369; GeneDx pers. comm.).
PP3
REVEL score is 0.81, all predictors predict deleterious
PM1
Variant is located within in the domain ClinGen working group: within myosin motor domain; residues 181-937
PM2
FAF at 0.95 confidence: 0.00001122 Used 4/113682 from European (non-Finnish) subpopulation
Not Met criteria codes
BS3
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
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
BP5
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
PM5
NM_000257.4(MYH7):c.2081G>A (p.Arg694His): 2* P/LP in ClinVar At best has LP based on PS4_Moderate/Strong, PM2_Supporting, PM1, PP3 No comment on de novo data in ClinVar
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