Submissions for variant NM_002471.4(MYH6):c.3427C>T (p.Arg1143Trp)

gnomAD frequency: 0.00006  dbSNP: rs755209382

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002458509	SCV002615551	uncertain significance	Cardiovascular phenotype	2023-06-17	criteria provided, single submitter	clinical testing	The p.R1143W variant (also known as c.3427C>T), located in coding exon 24 of the MYH6 gene, results from a C to T substitution at nucleotide position 3427. The arginine at codon 1143 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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	RCV002488353	SCV002776307	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2022-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568881	SCV003254713	uncertain significance	Hypertrophic cardiomyopathy 14	2024-04-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1143 of the MYH6 protein (p.Arg1143Trp). This variant is present in population databases (rs755209382, gnomAD 0.009%). 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: 1175107). 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.
GeneDx	RCV001529955	SCV005421839	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with hypertrophic cardiomyopathy undergoing whole exome sequencing (PMID: 25351510); This variant is associated with the following publications: (PMID: 25351510)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529955	SCV001744342	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529955	SCV001954991	uncertain significance	not provided		no assertion criteria provided	clinical testing