ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu) (rs727504310)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000758036 SCV000564432 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2539A>G (p.Lys847Glu) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:10725281; PMID:20031618; PMID:23271734; PMID:23782526; Partners LMM ClinVar SCV000204039.4). This variant was absent from large population studies (PM2; This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000758036 SCV000204039 likely pathogenic Hypertrophic cardiomyopathy 2021-03-31 criteria provided, single submitter clinical testing The p.Lys847Glu variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (Fananapazir 1999 PMID: 10328076, Atiga 2000 PMID: 10725281, Kaski 2009 PMID: 20031618, Leung 2013 PMID: 23271734, Nunez 2013 PMID: 23782526, Walsh 2017 PMID: 27532257, Kelly 2018 PMID: 29300372, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID 27532257). Finally, this variant was classified as Likely Pathogenic on December 15, 2016 by the ClinGen-approved Inherited Cardiomyopathy Variant Curation expert panel (Variation ID 177757). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PS4, PM1, PM2_Supporting, PP3.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000168873 SCV000256634 likely pathogenic Familial hypertrophic cardiomyopathy 1 2015-04-22 criteria provided, single submitter research The MYH7 Lys847Glu variant has been reported in multiple unrelated HCM patients (Atiga 2000 , Kaski 2009, Aletras 2011, Brito 2012, Leung 2013, Nunez 2013) and was absent in large population studies of >200 normal controls (Brito D et al., 2012; Nunez L et al., 2013; Kaski J et al., 2009). This variant has been identified in childhood HCM (Kaski, 2009) as well as adult-onset HCM (see references). This variant is also absent from both the 1000 genomes project ( and the from the large Exome Aggregation Consortium dataset ( We have identified this variant in 1 HCM patient who has no family history of disease or SCD. Lysine (Lys) at position 847 is highly conserved across distantly related species, and in silico tools including SIFT, MutationTaster, and PolyPhen2, predict that the amino acid change to be "damaging". Additionally, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts that this MYH7 Lys847Glu variant is causative of the disease. Based on the absence of this variant in the general population, predictions from a number of in silico models, and the presence of this variant in multiple unrelated HCM patients in independent studies, we classify this variant as "likely pathogenic". Further supporting evidence such as segregation data and/or functional analysis will be required to reclassify this variant as pathogenic.
Ambry Genetics RCV000622211 SCV000740235 likely pathogenic Cardiovascular phenotype 2020-03-27 criteria provided, single submitter clinical testing The p.K847E variant (also known as c.2539A>G), located in coding exon 20 of the MYH7 gene, results from an A to G substitution at nucleotide position 2539. The lysine at codon 847 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been detected in multiple individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts that underwent HCM genetic testing (Kaski JP et al. Circ Cardiovasc Genet. 2009 Oct;2(5):436-41; Homburger JR et al. Proc Natl Acad Sci USA. 2016 06;113(24):6701-6; Walsh R et al. Genet Med. 2017 Feb;19(2):192-203; Kelly MA. Genet Med. 2018 03;20(3):351-359). Furthermore, this alteration is located at the head-tail junction in the S2 domain (Alamo L et al. Elife. 2017 Jun;6:e24634). 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 majority of evidence to date, this variant is likely to be pathogenic.
Invitae RCV000758036 SCV000948267 pathogenic Hypertrophic cardiomyopathy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 847 of the MYH7 protein (p.Lys847Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 22857948, 28615295, 23782526, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177757). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194066 SCV001363321 pathogenic Primary familial hypertrophic cardiomyopathy 2019-10-07 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2539A>G (p.Lys847Glu) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252322 control chromosomes. c.2539A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example Atiga_2007, Brito_2012, Kaski_2009, Leung_2013, Marston_2013, Nunez_2013, Homburger_2016, Walsh_2017, Ross_2017). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Leung_2013, Marston_2013). Four clinical diagnostic laboratories and one expert panel (ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=4). The expert panel classification as likely pathogenic may represent an outdated submission (2016). Based on the evidence outlined above, the variant was classified as pathogenic.

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