Submissions for variant NM_002471.4(MYH6):c.4685G>A (p.Arg1562Gln)

gnomAD frequency: 0.00002  dbSNP: rs371068881

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000248233	SCV000319500	uncertain significance	Cardiovascular phenotype	2023-02-15	criteria provided, single submitter	clinical testing	The p.R1562Q variant (also known as c.4685G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4685. The arginine at codon 1562 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). 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	RCV001374351	SCV001571176	uncertain significance	Hypertrophic cardiomyopathy 14	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1562 of the MYH6 protein (p.Arg1562Gln). This variant is present in population databases (rs371068881, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 263944). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Clinical Genetics, Academic Medical Center	RCV001795473	SCV002034482	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001795473	SCV002037230	uncertain significance	not provided		no assertion criteria provided	clinical testing