ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.1702C>T (p.Arg568Cys)

gnomAD frequency: 0.00006  dbSNP: rs149650190
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154763 SCV000204443 uncertain significance not specified 2014-11-06 criteria provided, single submitter clinical testing The p.Arg568Cys variant in MYH6 has been reported in 1 Hispanic individual with DCM (Hershberger 2010) and has been identified in 1/8600 European American chrom osomes and 1/4406 African American chromosomes by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS/; dbSNP rs149650190). Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Arg5 68Cys variant is uncertain.
Invitae RCV000460717 SCV000546164 uncertain significance Hypertrophic cardiomyopathy 14 2023-11-07 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 568 of the MYH6 protein (p.Arg568Cys). This variant is present in population databases (rs149650190, gnomAD 0.02%). This missense change has been observed in individual(s) with peripartum cardiomyopathy or cardiac arrest (PMID: 20215591, 30282064). ClinVar contains an entry for this variant (Variation ID: 178072). 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 with a positive predictive value of 80%. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000845511 SCV000987614 uncertain significance Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154763 SCV002014942 likely benign not specified 2021-10-17 criteria provided, single submitter clinical testing Variant summary: MYH6 c.1702C>T (p.Arg568Cys) results in a non-conservative amino acid change located in the Head domain (Posch_2011) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251458 control chromosomes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1702C>T has been reported in the literature. A cross section of ascertainments include, an individual with peripartum cardiomyopathy who was subsequently cited by another study (example, Morales_2010 and Hershberger_2010), in controls cohorts within the ESP database (Andreasen_2013), in a study cohort of DCM families (example, Chami_2014), as a non-segregating VUS variant in a family with hypertrophic cardiomyopathy and a causative variant in the MYBPC3 gene (Williams_2018, see below). These data do not allow any conclusion about variant significance. At-least one co-occurrence with another causative pathogenic variant has been reported (MYBPC3 g.11:47368998delA, p. Phe295SerfsTer5, Williams_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping but not all the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV002399544 SCV002714168 uncertain significance Cardiovascular phenotype 2023-05-19 criteria provided, single submitter clinical testing The p.R568C variant (also known as c.1702C>T), located in coding exon 13 of the MYH6 gene, results from a C to T substitution at nucleotide position 1702. The arginine at codon 568 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in cohorts with dilated cardiomyopathy, left ventricular non-compaction cardiomyopathy, and hypertrophic cardiomyopathy; however, in some cases, clinical details were limited or additional variants in cardiac-related genes were also detected (Hershberger RE et al. Circ Cardiovasc Genet. 2010;3:155-61l; Mates J et al. Eur. J. Hum. Genet. 2018 07;26(7):1014-1025; Williams N et al. Cardiovasc Pathol. 2018 Sep;37:30-33; Mazzarotto F et al. Genet Med. 2021 May;23(5):856-864; Ware SM et al. Am J Hum Genet. 2022 Feb;109(2):282-298). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet. 2013;21:918-28). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.