Submissions for variant NM_000257.4(MYH7):c.3830G>C (p.Arg1277Pro)

dbSNP: rs397516195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208514	SCV000264088	uncertain significance	Left ventricular noncompaction cardiomyopathy	2015-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000439310	SCV000536634	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The R1277P variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1277P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while a missense variant in the same residue (R1277Q) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810770	SCV000951003	uncertain significance	Hypertrophic cardiomyopathy	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1277 of the MYH7 protein (p.Arg1277Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 30471092, 35527761). ClinVar contains an entry for this variant (Variation ID: 222726). 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 MYH7 protein function with a positive predictive value of 95%. 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	RCV002354588	SCV002621640	uncertain significance	Cardiovascular phenotype	2017-05-10	criteria provided, single submitter	clinical testing	The p.R1277P variant (also known as c.3830G>C), located in coding exon 26 of the MYH7 gene, results from a G to C substitution at nucleotide position 3830. The arginine at codon 1277 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is not 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.
Revvity Omics, Revvity	RCV000439310	SCV003817697	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320138	SCV003835151	uncertain significance	Myosin storage myopathy	2022-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000439310	SCV004129090	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MYH7: PM2, PM5