Submissions for variant NM_000257.4(MYH7):c.5536C>T (p.Arg1846Cys)

gnomAD frequency: 0.00001  dbSNP: rs12590294

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048116	SCV001212105	uncertain significance	Hypertrophic cardiomyopathy	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1846 of the MYH7 protein (p.Arg1846Cys). This variant is present in population databases (rs12590294, gnomAD 0.006%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20800588, 27247418, 29709087). ClinVar contains an entry for this variant (Variation ID: 161321). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001185061	SCV001351201	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1846 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 20800588) and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087). This variant has been identified in 3/248286 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.
All of Us Research Program, National Institutes of Health	RCV001185061	SCV004814347	uncertain significance	Cardiomyopathy	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1846 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 20800588), in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087), and in one individual affected with idiopathic ventricular fibrillation (PMID: 37653714). This variant has been identified in 3/248286 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.
Ambry Genetics	RCV004984682	SCV005453780	uncertain significance	Cardiovascular phenotype	2024-11-13	criteria provided, single submitter	clinical testing	The p.R1846C variant (also known as c.5536C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5536. The arginine at codon 1846 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individuals in a hypertrophic cardiomyopathy cohort and a ventricular fibrillation cohort, but clinical details were limited (Millat G et al. Clin Chim Acta, 2010 Dec;411:1983-91; Jeong JH et al. Korean Circ J, 2023 Oct;53:693-707). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
CSER _CC_NCGL, University of Washington	RCV000148700	SCV000190429	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research