ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly) (rs397516161)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162341 SCV000212641 pathogenic Familial hypertrophic cardiomyopathy 1 2017-04-10 criteria provided, single submitter research This MYH7 Glu894Gly variant has previously been identified in multiple HCM cohorts (Yu B, et al., 2005; Gruner C, et al., 2011; Lopes LR, et al., 2013; Kapplinger JD, et al., 2014; Walsh R et al., 2017). This variant was first described by Van Driest et al. (2004) in multiple HCM patients, one of whom was a carrier of a second variant in MYBPC3 and presented with a more severe phenotype (Van Driest SL, et al., 2004). The MYH7 Glu894Gly variant is extremely rare in the general population; it is absent in both the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 7 HCM probands in our cohort. Genetic analysis was available for 2 families. In one family the variant was shown to co-segregate with disease in 4 affected members. This family also carries a VUS (TNNT2 Arg278Cys). In the second family the variant was found to segregate to one other affected family member (5 meioses in total). Computational tools SIFT, PolyPhen-2 and MutationTaster predict the Glu894Gly variant to be deleterious. Additionally, Polyphen-HCM (Jordan DM, et al., 2011) predicts that MYH7 Glu894Gly is deleterious. Furthermore, we have recently published ancestry studies to show our unrelated probands share a common haplotype, suggesting this may be a founder in the Australian population (Ross SB et al. 2017). Based on this data we classify MYH7 Glu894Gly as "pathogenic".
Ambry Genetics RCV000242919 SCV000317861 pathogenic Cardiovascular phenotype 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Blueprint Genetics, RCV000223927 SCV000927960 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000198644 SCV000564436 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2681A>G (p.Glu894Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:PMID:27532257; PMID:15358028; PMID:15858117; PMID:21511876; PMID:23396983; PMID:24510615; SHaRe consortium, PMID: 30297972, Partners LMM ClinVar SCV000059463.5; AGCMC Sydney ClinVar SCV000212641.2; Invitae ClinVar SCV000253683.5). This variant segregated with disease in 6 affected individuals (PP1_Moderate: AGCMC Sydney ClinVar SCV000212641.2; Partners LMM ClinVar SCV000059463.5). This variant was absent from large population studies (PM2; http://exac.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 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3
GeneDx RCV000223927 SCV000208494 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing The E894G pathogenic variant in the MYH7 gene has been previously reported in association with HCM (Van Driest et al., 2004; Yu et al., 2005; Tsoutsman et al., 2008; Gruner et al., 2011; Lopes et al., 2013; Kapplinger et al., 2014; Homburger et al., 2016; Walsh et al., 2017). Additionally, this variant is classified as a pathogenic variant in ClinVar by the ClinGen Inherited Cardiomyopathy Expert Panel, where E894G is noted to be present in a significant number of affected individuals and has been shown to segregate with disease in multiple affected relatives (ClinVar SCV000564436.1; Landrum et al., 2016). Moreover, E894G 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. Furthermore, 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. Finally, the E894G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000198644 SCV000253683 pathogenic Hypertrophic cardiomyopathy 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 894 of the MYH7 protein (p.Glu894Gly). 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 (ExAC no frequency). This variant has been reported in the literature in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15858117, 21511876, 15358028, 26914223, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 42922). 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) 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000198644 SCV000059463 pathogenic Hypertrophic cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing The p.Glu894Gly variant in MYH7 has been identified in >15 individuals with HCM and segregated with disease in 5 affected relatives from 2 families (Van Driest 2004a, Van Driest 2004b, Yu 2005, Gruner 2011, Lopes 2013, Kapplinger 2014, LMM data, Agnes Ginges Centre for Molecular Cardiology data - ClinVar SCV000212641.1 ). One of these individuals had a second variant in MYBPC3 and presented at an e arlier age with a more severe phenotype. This variant was absent from large popu lation studies. Computational prediction tools and conservation analysis are con sistent with pathogenicity. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In addition, this var iant was classified as pathogenic on December 15, 2016 by the ClinGen-approved I nherited Cardiomyopathy expert panel (ClinVar SCV000564436.2). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal do minant manner based upon segregation studies, absence from controls, and prevale nce in affected individuals. ACMG/AMP Criteria applied: PS4; PM1; PM2; PP1_Moder ate; PP3.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000257928 SCV000740376 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-10-11 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223927 SCV000280332 likely pathogenic not provided 2014-08-27 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu894Gly (c.2681A>G) This variant has been seen in at least 15 unrelated cases of HCM (not including this patient). There is no published segregation data. Van Driest et al. (2004) observed this variant in 3 unrelated individuals with HCM. These three cases are likely redundant with a later reports by that group, however there does appear to be an additional case in those reports (Kapplinger et al 2014, Bos et al 2014). Yu et al. (2005) found this variant in 3 unrelated Australian probands with HCM. Gruner et al. (2011) reported it in one patient with apical HCM from their Toronto cohort. Captur et al (2014) included a patient with HCM and this variant in a study comparing imaging findings in carriers with and without left ventricular hypertrophy. Subjects were recruited from the UCL HCM clinic in London. We have seen this variant in one other patient with HCM in our center. She was diagnosed with HCM at 4 months of age and has a severe phenotype. She had a multi-gene sequencing panel with no other variants found. She has a strong family history of HCM. Presumably LMM and GeneDx have seen this variant in patients, since they have submitted it to Clinvar, however that data is not available in ClinVar. I spoke to LMM directly and they shared that they have seen the variant in 5 families with HCM and in one family another affected relative had the variant. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Leu889His, Ala893Val, Ala901Gly, Ala901Pro, Glu903Gly, Glu903Lys (HGMD via GeneDx). This is a non-conservative amino acid change from a negatively charged glutamic acid residue to a neutral, nonpolar glycine. The glutamic acid at codon 894 is highly conserved across 43/44 vertebrate species examined (it is a serine in lamprey). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.992. The Invitae report notes that 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)". This is an algorithm developed by LMM and their colleagues. In total this variant has not been seen in ~6800 individuals from published controls and publicly available population datasets. Van Driest et al. (2004) did not find it in 100 control individuals of Caucasian descent or 100 control individuals of African-American descent. Yu et al. (2005) did not find it in 100 ethnicity-matched control individuals. No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 4/1/2013). No variation at this codon is present in dbSNP or in 1000 genomes. GeneDx did not report internal controls. There is no variation at codon 984 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of March 24th, 2015).

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