Submissions for variant NM_000257.4(MYH7):c.2135G>T (p.Arg712Leu)

gnomAD frequency: 0.00001  dbSNP: rs1224554825

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001871003	SCV002135883	likely pathogenic	Hypertrophic cardiomyopathy	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 712 of the MYH7 protein (p.Arg712Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 10679957). ClinVar contains an entry for this variant (Variation ID: 1370458). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 33605878). This variant disrupts the p.Arg712 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28855170). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002422932	SCV002729057	uncertain significance	Cardiovascular phenotype	2021-02-25	criteria provided, single submitter	clinical testing	The p.R712L variant (also known as c.2135G>T), located in coding exon 17 of the MYH7 gene, results from a G to T substitution at nucleotide position 2135. The arginine at codon 712 is replaced by leucine, an amino acid with dissimilar properties. This alteration is reported in a family with hypertrophic cardiomyopathy (HCM) (Sakthivel S et al. Hum Mutat, 2000 Mar;15:298-9). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003597234	SCV004244648	pathogenic	MYH7-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	PS3, PM5, PM1, PP3, PP2
GeneDx	RCV004815695	SCV005439224	likely pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: BaruaB2019[Abstract], 35216312, 38708944, 33605878, 27532257, 29300372, 10679957)