Submissions for variant NM_002471.4(MYH6):c.2611C>T (p.Arg871Cys)

gnomAD frequency: 0.00014  dbSNP: rs376682837

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037460	SCV000061118	uncertain significance	not specified	2012-05-15	criteria provided, single submitter	clinical testing	The Arg871Cys variant (MYH6) has been identified in 1/7020 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/). Note this could represent a presymptomatic individua l. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. Additional studies are needed to fully assess its clinical si gnificance.
GeneDx	RCV000656919	SCV000490649	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	Reported in patients with cardiomyopathy, HCM, and Brugada syndrome in the published literature (PMID: 32004434, 28082330, 26220970); 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: 26220970, 28082330, 32004434)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551495	SCV000648236	uncertain significance	Hypertrophic cardiomyopathy 14	2025-02-02	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 871 of the MYH6 protein (p.Arg871Cys). This variant is present in population databases (rs376682837, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 44469). 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) has been performed 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 MYH6 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.
Ambry Genetics	RCV000618162	SCV000736963	uncertain significance	Cardiovascular phenotype	2022-09-06	criteria provided, single submitter	clinical testing	The p.R871C variant (also known as c.2611C>T), located in coding exon 19 of the MYH6 gene, results from a C to T substitution at nucleotide position 2611. The arginine at codon 871 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005003431	SCV000896379	uncertain significance	Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2024-01-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770453	SCV000901896	uncertain significance	Cardiomyopathy	2016-04-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656919	SCV001715060	uncertain significance	not provided	2019-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037460	SCV002600705	uncertain significance	not specified	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2611C>T (p.Arg871Cys) results in a non-conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251462 control chromosomes (gnomAD). The observed variant frequency is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy (2.5e-05), suggesting that the variant is benign. c.2611C>T has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with Brugada syndrome and in an individual with hypertrophic cardiomyopathy (e.g. Di Resta_2015, Walsh_2017). The variant has also been reported in two affected individuals from a hypertrophic cardiomyopathy family, however both individuals also had a co-occurring variant (MYL2 c.496G>C, p.Asp166His) which segregated with the disease phenotype within the family (e.g. De Bortoli_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000656919	SCV005199373	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656919	SCV001550927	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH6 p.Arg871Cys variant was not identified in the literature but was identified in dbSNP (ID: rs376682837), Cosmic, LOVD 3.0 (classified as a VUS) and ClinVar (classified as a VUS by Laboratory for Molecular Medicine, Invitae, Ambry Genetics, Fulgent Genetics, GeneDx and CHEO Genetics Diagnostic Laboratory). The variant was identified in control databases in 24 of 282854 chromosomes at a frequency of 0.000085 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7228 chromosomes (freq: 0.000415), South Asian in 7 of 30616 chromosomes (freq: 0.000229), African in 2 of 24972 chromosomes (freq: 0.00008), European (non-Finnish) in 10 of 129160 chromosomes (freq: 0.000077), East Asian in 1 of 19952 chromosomes (freq: 0.00005) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004); it was not observed in the Latino and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg871 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.