Submissions for variant NM_000257.4(MYH7):c.2543A>G (p.Glu848Gly)

dbSNP: rs727504311

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461430	SCV000204041	likely pathogenic	Hypertrophic cardiomyopathy	2018-05-10	criteria provided, single submitter	clinical testing	The p.Glu848Gly variant in MYH7 has been identified in at least 6 individuals wi th HCM and segregated with disease in one affected family member (Alfares 2015, GeneDx pers. comm., LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that the p.Glu848Gly va riant may impact protein function (Pioner 2016); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Glu848Gly variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. Of note, this variant lies in the head region of the protein. Missense vari ants in this region have been reported and statistically indicated to be more li kely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu848Gly variant i s likely pathogenic. ACMG/AMP criteria applied: PM1, PM2, P23_Moderate, PS4_Mode rate, PP3.
GeneDx	RCV000158548	SCV000208483	likely pathogenic	not provided	2020-06-22	criteria provided, single submitter	clinical testing	Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 177758; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Functional studies using stem cells suggest that this variant changes contractile properties leading to cardiomyopathy (Pioner et al., 2016; Yang et al., 2018); 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: 27532257, 27161364, 25611685, 28606303, 30623132)
Invitae	RCV000461430	SCV000546264	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 848 of the MYH7 protein (p.Glu848Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27161364, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 177758). 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: 30623132). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000770756	SCV000696342	pathogenic	Primary familial hypertrophic cardiomyopathy	2019-02-05	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2543A>G (p.Glu848Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246248 control chromosomes (gnomAD). It is reported in the Atlas of Cardiac Genetic Variation database to occur in the region enriched for HCM mutations (residues 181-937) and is scored with a high etiological fraction (0.97) (in general, missense variants in MYH7 have an overall etiological fraction of 0.92). c.2543A>G has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy (Alfares_2015) and was shown to co-segregate with disease in a pedigree affected with familial cardiomyopathy (FCM) with adult-onset systolic dysfunction (Yang_2018). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function report this variant to result in contractile dysfunction of myofibrils (Pioner_2016) by disruption of the myosin S2 and cMyBP-C C1C2 protein-protein interaction (Yang_2018; Pioner_2016) on measures of maximal isometric tension generation (Pioner_2016) and lack of growth in yeast-two hybrid assay (Yang_2018). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.