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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.610C>T (p.Arg204Cys)

CA016540

181315 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c7cf0cae-5bda-4efd-9e96-fbcf8922fc1b
Approved on: 2021-04-21
Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.610C>T
NM_000257.4(MYH7):c.610C>T (p.Arg204Cys)
NC_000014.9:g.23431790G>A
CM000676.2:g.23431790G>A
NC_000014.8:g.23900999G>A
CM000676.1:g.23900999G>A
NC_000014.7:g.22970839G>A
NG_007884.1:g.8872C>T
ENST00000355349.4:c.610C>T
ENST00000355349.3:c.610C>T
NM_000257.3:c.610C>T
More

Uncertain Significance

Met criteria codes 3
PM1 PM2 PS4_Supporting
Not Met criteria codes 13
PS3 PS1 PS2 PP1 PP3 PM6 BS4 BS3 BS1 BP5 BP2 BP4 BA1

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.610C>T (p.Arg204Cys) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.) and in 1 infant with LVH/RVH and other complex heart disease (GeneDx pers. comm.). This variant was identified in 0.0026% (FAF 95% CI; 3/30616) South Asian 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 were mixed about the potential impact of this variant. 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_Supporting, PM2, PM1.
Met criteria codes
PM1
hotspot/functional domain is between 181-937
PM2
Variant is seen in 0.0026% (FAF 95% CI; 3/30616) South Asian chromosomes
PS4_Supporting
Detected by GeneDx in 1 proband with HCM and in 1 infant with LVH/RVH, R pulm art stenosis, pulm and aortic valve stenosis Detected by Invitae in 1 HCM proband with a VUS another cardiomyopathy gene Homburger et al. 2016 (PMID: 27247418): detected in 1 participant in SHARE population (population of HCM) Walsh et al. 2017 (PMID: 27532257): Oxford detected in 1/3200 HCM cases Would consider this a total of at least 3 probands with consistent phenotype & 1 with complex phenotype No additional references found
Not Met criteria codes
PS3
No functional studies
PS1
NM_000257.4(MYH7):c.611G>T (p.Arg204Leu) - Conflicting in ClinVar NM_000257.4(MYH7):c.611G>A (p.Arg204His) - Conflicting in ClinVar, but reported in >15 individuals; Old VCEP curation (never reviewed/approved) is LP and based on evidence in ClinVar LP seems most appropriate - therefore not completing full assessment due to low likelihood of variant being P. NM_000257.4(MYH7):c.610C>A (p.Arg204Ser) - VUS in ClinVar
PS2
No de novo instances reported
PP1
No families evaluated
PP3
REVEL score of 0.71; computational tools are mixed; amino acid and immediate region is poorly conserved outside of mammals
PM6
No de novo instances reported
BS4
No families evaluated
BS3
No functional studies
BS1
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
BP2
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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