Submissions for variant NM_002471.4(MYH6):c.2086C>T (p.Arg696Cys)

gnomAD frequency: 0.00001  dbSNP: rs778886029

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219216	SCV000272019	uncertain significance	not specified	2015-08-25	criteria provided, single submitter	clinical testing	The p.Arg696Cys variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs778886029). Computational prediction tools and conservation analysis suggest that the p.Arg696Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Arg696Cys variant is uncertain.
Ambry Genetics	RCV002415902	SCV002727817	uncertain significance	Cardiovascular phenotype	2021-05-21	criteria provided, single submitter	clinical testing	The p.R696C variant (also known as c.2086C>T), located in coding exon 16 of the MYH6 gene, results from a C to T substitution at nucleotide position 2086. The arginine at codon 696 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470822	SCV002767387	uncertain significance	Atrial septal defect 3	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however gain of function has been suggested (PMID: 20656787). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin head (motor domain) (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been reported as a VUS (ClinVar, LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV003629107	SCV004531710	uncertain significance	Hypertrophic cardiomyopathy 14	2022-11-24	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs778886029, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 696 of the MYH6 protein (p.Arg696Cys). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. 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: 228889).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723799	SCV001958559	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723799	SCV001975865	uncertain significance	not provided		no assertion criteria provided	clinical testing