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

dbSNP: rs727504310

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758036	SCV000564432	pathogenic	Hypertrophic cardiomyopathy	2021-11-30	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu) variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). This variant segregated with disease in 7 affected individuals with HCM in 5 families (PP1_Strong; Ross 2017 PMID:28615295; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). 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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PM1.
Laboratory for Molecular Medicine, Mass General Brigham 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	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 (http://www.1000genomes.org/) and the from the large Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). 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	pathogenic	Cardiovascular phenotype	2021-11-22	criteria provided, single submitter	clinical testing	The p.K847E pathogenic mutation (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 is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been detected in multiple individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts that underwent HCM genetic testing (Atiga WL et al. Circulation. 2000 Mar;101(11):1237-42; Kaski JP et al. Circ Cardiovasc Genet. 2009 Oct;2(5):436-41; Núñez L et al. Circ J. 2013 Jun;77(9):2358-65; Lopes LR. Heart et al. 2015 Feb;101(4):294-301; 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; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000758036	SCV000948267	pathogenic	Hypertrophic cardiomyopathy	2024-01-05	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 847 of the MYH7 protein (p.Lys847Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 20031618, 22857948, 23782526, 27247418, 27532257, 28615295). ClinVar contains an entry for this variant (Variation ID: 177757). 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%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798497	SCV002042276	pathogenic	Cardiomyopathy	2022-09-14	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000168873	SCV002769183	pathogenic	Hypertrophic cardiomyopathy 1	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established However, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid (exon 22). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 29300372). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as disease causing in multiple individuals (ClinVar, PMID: 29300372, 28408708). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign