ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2543A>G (p.Glu848Gly) (rs727504311)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2017-09-08 criteria provided, single submitter clinical testing The E848G variant that is likely pathogenic was identified in the coiled coil region of the MYH7 gene. This variant has been reported by an external laboratory as a variant of uncertain significance, but no clinical or segregation information is available. Alternatively, E848G has been identified in several individuals with HCM referred for genetic testing of HCM at GeneDx. However, the information obtained from testing of these individuals is not sufficient, and additional family studies are essential for full interpretation. The E848G variant has not been observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). The E848G 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. Additionally, 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. Missense variants in nearby residues (E846Q, M849T) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. A functional study focusing on myofibril properties demonstrated E848G may have caused marked impairment of maximal isometric tension generation as well as an increased rate of acto-myosin cross-bridge turnover, nonetheless it is possible that the observed changes are not totally due to the affect of the variant (Pioner et al., 2016). Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, informative segregation analysis and definitive functional evidence is required.
Invitae RCV000461430 SCV000546264 likely pathogenic Hypertrophic cardiomyopathy 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 848 of the MYH7 protein (p.Glu848Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (rs727504311, ExAC no frequency). This variant has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 27161364, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177758). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). Experimental studies have shown that cardiomyocytes derived from an individual with hypertrophic cardiomyopathy who carried this variant had abnormalities at the myofibril level (PMID: 27161364). In summary, this variant is a missense change that that is absent from population databases, has been observed in several affected individuals, is predicted to be deleterious by a well characterized algorithm, and may have an effect on cardiomyocyte function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.