Submissions for variant NM_002471.4(MYH6):c.4829G>A (p.Arg1610His)

gnomAD frequency: 0.00003  dbSNP: rs758792342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314131	SCV001504649	uncertain significance	Hypertrophic cardiomyopathy 14	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1610 of the MYH6 protein (p.Arg1610His). This variant is present in population databases (rs758792342, gnomAD 0.01%). 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: 312849). 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	RCV002225585	SCV002503999	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002338894	SCV002635077	uncertain significance	Cardiovascular phenotype	2023-12-03	criteria provided, single submitter	clinical testing	The p.R1610H variant (also known as c.4829G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4829. The arginine at codon 1610 is replaced by histidine, an amino acid with highly similar properties. A different variant affecting this codon (p.R1610C, c.4828C>T) has been detected in an individual with atrial and and ventricular septal defects (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). 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	RCV002480128	SCV002792050	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-10-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002225585	SCV004129064	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing