Submissions for variant NM_000257.4(MYH7):c.1504A>G (p.Lys502Glu)

dbSNP: rs876657877

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218204	SCV000272033	uncertain significance	not specified	2015-03-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys502Glu variant in MYH7 has not been previously reported in individuals with cardiomyop athy or in large population studies. Lysine (Lys) at position 502 is highly cons erved in mammals and across evolutionarily distant species and the change to glu tamic acid (Glu) was predicted to be pathogenic using a computational tool clini cally validated by our laboratory. This tool's pathogenic prediction is estimate d to be correct 94% of the time (Jordan 2011). In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Lys502Glu var iant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628909	SCV000749817	uncertain significance	Hypertrophic cardiomyopathy	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 502 of the MYH7 protein (p.Lys502Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 228899). 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 MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
GeneDx	RCV001753645	SCV002007421	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	Identified in a patient with DCM in published literature (PMID: 37652022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27532257, 29300372, 37652022)
Ambry Genetics	RCV004984754	SCV005453846	uncertain significance	Cardiovascular phenotype	2024-11-05	criteria provided, single submitter	clinical testing	The p.K502E variant (also known as c.1504A>G), located in coding exon 13 of the MYH7 gene, results from an A to G substitution at nucleotide position 1504. The lysine at codon 502 is replaced by glutamic acid, an amino acid with similar properties. This variant has been observed in at least one individual with a personal and/or family history consistent with dilated cardiomyopathy (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; 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. Based on the available evidence, the clinical significance of this variant remains unclear.