Submissions for variant NM_000257.4(MYH7):c.4816C>T (p.Arg1606Cys)

gnomAD frequency: 0.00001  dbSNP: rs200530211

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172042	SCV000051002	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154606	SCV000204279	uncertain significance	not specified	2016-09-12	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000172042	SCV000208606	uncertain significance	not provided	2024-09-06	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in association with HCM (PMID: 27532257, 25031304, 27688314, 27247418); Not observed at 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: 25031304, 27688314, 27247418, 28986452, 28606303, 27532257, 23861362, 37652022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470391	SCV000546188	uncertain significance	Hypertrophic cardiomyopathy	2024-12-30	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 1606 of the MYH7 protein (p.Arg1606Cys). This variant is present in population databases (rs200530211, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25031304, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177945). 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.
Illumina Laboratory Services, Illumina	RCV001112385	SCV001270041	uncertain significance	Hypertrophic cardiomyopathy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001112386	SCV001270042	uncertain significance	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV003320111	SCV001270043	uncertain significance	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001112388	SCV001270044	uncertain significance	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001184477	SCV001350450	uncertain significance	Cardiomyopathy	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1606 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). An experimental functional study has shown that this variant does not change mRNA and protein expression levels (PMID: 25031304). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25031304, 27532257, 28640247, 30297972) and in an individual affected with unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 2/251490 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	RCV002336317	SCV002637985	uncertain significance	Cardiovascular phenotype	2022-06-01	criteria provided, single submitter	clinical testing	The p.R1606C variant (also known as c.4816C>T), located in coding exon 32 of the MYH7 gene, results from a C to T substitution at nucleotide position 4816. The arginine at codon 1606 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals from hypertrophic cardiomyopathy cohorts; however, limited clinical detail was provided and some reports may overlap (Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Helms AS et al. Circ Cardiovasc Genet, 2014 Aug;7:434-43; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001184477	SCV004820421	uncertain significance	Cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1606 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). An experimental functional study has shown that this variant does not change mRNA and protein expression levels (PMID: 25031304). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25031304, 27532257, 28640247, 30297972) and in an individual affected with unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 2/251490 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	RCV004532746	SCV004753784	uncertain significance	MYH7-related disorder	2023-12-27	no assertion criteria provided	clinical testing	The MYH7 c.4816C>T variant is predicted to result in the amino acid substitution p.Arg1606Cys. This variant was reported in individuals with hypertrophic cardiomyopathy (Helms et al. 2014. PubMed ID: 25031304; Table S1, Homburger et al. 2016. PubMed ID: 27247418; Table S1B, Walsh et al. 2016. PubMed ID: 27532257). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.