Submissions for variant NM_002471.4(MYH6):c.4727G>A (p.Arg1576Gln)

gnomAD frequency: 0.00008  dbSNP: rs771898553

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481711	SCV000573165	uncertain significance	not provided	2017-02-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH6 gene. The R1576Q variant has been reported in one patient with HCM (Xu et al., 2015); however, no familial segregation information or functional studies were provided. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1576Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229254	SCV001401694	uncertain significance	Hypertrophic cardiomyopathy 14	2024-08-19	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 1576 of the MYH6 protein (p.Arg1576Gln). This variant is present in population databases (rs771898553, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset hypertrophic cardiomyopathy (PMID: 26573135). ClinVar contains an entry for this variant (Variation ID: 423462). 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.
Ambry Genetics	RCV002341148	SCV002635904	uncertain significance	Cardiovascular phenotype	2022-02-23	criteria provided, single submitter	clinical testing	The p.R1576Q variant (also known as c.4727G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4727. The arginine at codon 1576 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Xu J et al. Sci Rep, 2015 Nov;5:16609). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.