Submissions for variant NM_000257.4(MYH7):c.4537A>T (p.Thr1513Ser)

dbSNP: rs397516222

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035919	SCV000059570	uncertain significance	not specified	2015-12-18	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV001371585	SCV001568155	uncertain significance	Hypertrophic cardiomyopathy	2022-10-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 43025). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 20309391, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1513 of the MYH7 protein (p.Thr1513Ser). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.
GeneDx	RCV001775551	SCV002013077	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing	Identified in association with HCM; however, the patients reported also harbored the R719Q variant in the MYH7 gene (Van Driest et al., 2004; Harris et al., 2010). The phase of the MYH7 variants is not reported in Van Driest et al. (2004), but Harris et al. (2010) reports that the MYH7 variants are on the same allele (in cis); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 43025; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18761664, 15358028, 27532257, 20309391)
Color Diagnostics, LLC DBA Color Health	RCV001804759	SCV002053228	uncertain significance	Cardiomyopathy	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 1513 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15519027, 20309391, 27532257); three of them were compound heterozygous with another pathogenic variant, p.Arg719Gln (ClinVar Variation ID 14107). 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.