Submissions for variant NM_002471.4(MYH6):c.3583C>T (p.Arg1195Cys)

gnomAD frequency: 0.00003  dbSNP: rs769756450

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics and Genomics Program, Sidra Medicine	RCV001293070	SCV001434052	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002450865	SCV002613611	uncertain significance	Cardiovascular phenotype	2023-05-25	criteria provided, single submitter	clinical testing	The p.R1195C variant (also known as c.3583C>T), located in coding exon 24 of the MYH6 gene, results from a C to T substitution at nucleotide position 3583. The arginine at codon 1195 is replaced by cysteine, an amino acid with highly dissimilar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI:dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003629114	SCV004469113	uncertain significance	Hypertrophic cardiomyopathy 14	2023-10-12	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 1195 of the MYH6 protein (p.Arg1195Cys). This variant is present in population databases (rs769756450, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 312861). 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. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702000	SCV001928135	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702000	SCV001951896	uncertain significance	not provided		no assertion criteria provided	clinical testing