Submissions for variant NM_002471.4(MYH6):c.4595G>A (p.Arg1532His)

dbSNP: rs34330111

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602177	SCV000712614	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	The p.Arg1532His variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66736 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s34330111). Computational prediction tools and conservation analysis suggest tha t the p.Arg1532His variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Arg1532His variant is uncertain.
Invitae	RCV001326872	SCV001517925	uncertain significance	Hypertrophic cardiomyopathy 14	2024-01-03	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 1532 of the MYH6 protein (p.Arg1532His). This variant is present in population databases (rs34330111, 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: 505418). 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	RCV001755988	SCV001997761	uncertain significance	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 505418; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV002341539	SCV002636334	uncertain significance	Cardiovascular phenotype	2021-11-24	criteria provided, single submitter	clinical testing	The p.R1532H variant (also known as c.4595G>A), located in coding exon 30 of the MYH6 gene, results from a G to A substitution at nucleotide position 4595. The arginine at codon 1532 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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.