ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited 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 2017-08-07 criteria provided, single submitter clinical testing The p.Lys847Glu variant in MYH7 has been reported in >15 individuals with HCM (F ananapazir 1999, Atiga 2000 , Kaski 2009, Leung 2013, Nunez 2013, LMM unpublishe d), and was absent large population studies (dbSNP rs727504310). Lysine (Lys) at position 847 is highly conserved in evolution and the change to glutamic acid ( Glu) was predicted to be pathogenic using a computational tool clinically valida ted by our laboratory. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statist ically indicated to be more likely to cause disease (Walsh 2016). In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Lys847Glu variant is likely pathogenic
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 2019-06-03 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000758036 SCV000948267 pathogenic Hypertrophic cardiomyopathy 2018-08-20 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.

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