Submissions for variant NM_000257.4(MYH7):c.3475G>A (p.Val1159Met)

gnomAD frequency: 0.00002  dbSNP: rs730880776

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158608	SCV000208543	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing	The V1159M variant in the MYH7 gene has been reported previously in 4 individuals with hypertrophic cardiomyopathy; however familial segregation and additional clinical information was not provided, and is unknown whether these individuals were found to harbor variants in other genes associated with hypertrophic cardiomyopathy (Walsh et al., 2017). The V1159M variant is not observed in large population cohorts (Lek et al., 2016). The V1159M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret V1159M as a variant of uncertain significance.
Invitae	RCV001248603	SCV001422102	uncertain significance	Hypertrophic cardiomyopathy	2022-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1159 of the MYH7 protein (p.Val1159Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181224). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002453545	SCV002613097	uncertain significance	Cardiovascular phenotype	2022-08-31	criteria provided, single submitter	clinical testing	The p.V1159M variant (also known as c.3475G>A), located in coding exon 25 of the MYH7 gene, results from a G to A substitution at nucleotide position 3475. The valine at codon 1159 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203; Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000158608	SCV003817764	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531997	SCV004356867	uncertain significance	Cardiomyopathy	2022-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1159 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 4 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.