Submissions for variant NM_002471.4(MYH6):c.4828C>T (p.Arg1610Cys)

gnomAD frequency: 0.00009  dbSNP: rs780726611

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219757	SCV000272028	uncertain significance	not specified	2015-06-24	criteria provided, single submitter	clinical testing	The p.Arg1610Cys variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66740 European American chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ). Arginine (Arg) at position 1610 is not conserved in evolution and 1 mammal (m anatee) carries a cysteine (Cys) at this position, raising the possibility that this change may be tolerated. However, additional computational prediction tools suggest that the p.Arg1610Cys variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Arg1610Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468191	SCV000546139	uncertain significance	Hypertrophic cardiomyopathy 14	2023-09-11	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 1610 of the MYH6 protein (p.Arg1610Cys). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 228895). This missense change has been observed in individual(s) with congenital heart disease, dilated cardiomyopathy, or left ventricular noncompaction (PMID: 28991257, 30471092, 32746448). This variant is present in population databases (rs780726611, gnomAD 0.005%).
Ambry Genetics	RCV002338682	SCV002639184	uncertain significance	Cardiovascular phenotype	2022-09-07	criteria provided, single submitter	clinical testing	The p.R1610C variant (also known as c.4828C>T), located in coding exon 31 of the MYH6 gene, results from a C to T substitution at nucleotide position 4828. The arginine at codon 1610 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in a congenital heart defect exome cohort, in one individual who had atrial and septal cardiac defects (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485392	SCV002785929	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-10-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001573798	SCV003815389	uncertain significance	not provided	2021-09-08	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004820839	SCV005442242	uncertain significance	Atrial septal defect 3	2024-12-19	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573798	SCV001800178	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001573798	SCV001807554	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532760	SCV004742386	uncertain significance	MYH6-related disorder	2024-01-18	no assertion criteria provided	clinical testing	The MYH6 c.4828C>T variant is predicted to result in the amino acid substitution p.Arg1610Cys. This variant was reported in the homozygous state in an individual with atrial and ventricular septal defects (Patient 1-07343 in Tables S1 and S3, Jin et al. 2017. PubMed ID: 28991257). This variant was also documented in individuals with dilated cardiomyopathy and left ventricular noncompaction (Table S2, Richard et al. 2019. PubMed ID: 30471092; Table S2, Cambon-Viala et al. 2021. PubMed ID: 34088380; Table S2, Burstein et al. 2021. PubMed ID: 32746448). However, no additional studies were performed to help assess the pathogenicity of this variant. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228895/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.