Submissions for variant NM_000257.4(MYH7):c.5089C>T (p.Arg1697Trp)

gnomAD frequency: 0.00001  dbSNP: rs1282833804

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371760	SCV001568339	uncertain significance	Hypertrophic cardiomyopathy	2020-06-21	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 1697 of the MYH7 protein (p.Arg1697Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.
GeneDx	RCV003235566	SCV003933334	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Identified in a patient with DCM in the published literature (Haas et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34542152, 25163546)
All of Us Research Program, National Institutes of Health	RCV004006830	SCV004826111	uncertain significance	Cardiomyopathy	2024-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1697 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 1/251178 chromosomes 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.
PreventionGenetics, part of Exact Sciences	RCV004757419	SCV005353586	uncertain significance	MYH7-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The MYH7 c.5089C>T variant is predicted to result in the amino acid substitution p.Arg1697Trp. This variant has been reported in two individuals with dilated cardiomyopathy (Table S6, Haas et al. 2015. PubMed ID: 25163546; Peña-Peña et al. 2021. PubMed ID: 32826072). This variant has also been reported in an individual without a personal history of hypertrophic cardiomyopathy (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.