Submissions for variant NM_000257.4(MYH7):c.2882T>G (p.Leu961Arg)

dbSNP: rs727504374

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000249682	SCV000320482	uncertain significance	Cardiovascular phenotype	2018-02-20	criteria provided, single submitter	clinical testing	The p.L961R variant (also known as c.2882T>G), located in coding exon 21 of the MYH7 gene, results from a T to G substitution at nucleotide position 2882. The leucine at codon 961 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in one individual reported to have hypertrophic cardiomyopathy (HCM) (Curila K, et al. Acta Cardiol 2012;67(1):23-9). Other alterations affecting the same amino acid, p.L961P (c.2882T>C) and p.L961V (c.2881C>G), have been reported in association with HCM (Bainbridge MN et al. Circ Cardiovasc Genet, 2015 Aug;8:544-52; Walsh R et al. Genet. Med. 2017;19:192-203).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 variant remains unclear.
GeneDx	RCV000497921	SCV000589386	uncertain significance	not specified	2017-06-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The L961R variant has been previously reported in at least one individual diagnosed with HCM (Curila et al., 2012), although no segregation data are available. The L961R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L961R 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. Furthermore, 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. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. Additionally, while missense variants at the same residue (L961P, L961V) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Bainbridge et al., 2015; Walsh et al., 2017), the clinical significance of these variants also remains to be definitively determined. Lastly, L961R is also classified as a variant of uncertain significance in ClinVar by a different clinical laboratory (ClinVar SCV000320482.1; Landrum et al., 2016).
Invitae	RCV001859467	SCV002299365	uncertain significance	Hypertrophic cardiomyopathy	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 961 of the MYH7 protein (p.Leu961Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22455086). ClinVar contains an entry for this variant (Variation ID: 264501). 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. 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.