ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met) (rs397516201)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000552931 SCV000564449 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:24093860; PMID:12707239; PMID:16858239; PMID:21239446; PMID:25031304; PMID:20624503; PMID:18533079; PMID:23674513; PMID:27532257; Partners LMM ClinVar SCV000059537.5; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; 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; PM2; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000552931 SCV000059537 likely pathogenic Hypertrophic cardiomyopathy 2017-10-10 criteria provided, single submitter clinical testing The p.Thr1377Met variant in MYH7 has been reported in > 35 individuals with HCM and segregated with the disease in 1 affected relative in 1 family (Richard 2003 , Van Driest 2004, Girolami 2006, Fokstuen 2008, Olivotto 2008, Millat 2010, Fok steun 2011, Witjas-Paalberends 2013, Adler 2014, Berge 2014, Helms 2014, Kapplin ger 2014, Walsh 2016, Song 2017, LMM data). This variant has been identified in 1/111706 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://; dbSNP rs397516201) and was classified as likely p athogenic on December 15, 2016 by the ClinGen Inherited Cardiomyopathy Expert Pa nel (ClinVar SCV000564449.2). Computational prediction tools and conservation an alysis suggest that the p.Thr1377Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Thr1377Met variant is likely pathogenic. ACMG/AMP Criteria applied: P S4, PM1, PP3 (Richards 2015).
GeneDx RCV000518840 SCV000208571 likely pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing The T1377M variant in the MYH7 gene has been reported in multiple unrelated individuals with HCM (Richard et al., 2003; Van Driest et al., 2004; Bos et al., 2006; Girolami et al., 2006; Olivotto et al., 2008; Fokstuen et al., 2008; Millat et al., 2010; Fokstuen et al., 2011; Witjas-Paalbernends et al., 2013; Witjas-Paalbernends et al., 2014; Kapplinger et al., 2014; Berge et al., 2014). Nevertheless, this variant was observed in two control individuals (Fokstuen et al., 2011) as well as multiple asymptomatic relatives of index cases (Witjas-Paalberends et al., 2014). Additionally, these publications do not provide family history information or segregation data. The T1377M variant was not observed at any significant frequency in large population cohorts (Lek et al., 2016).The T1377M 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, and this substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Blueprint Genetics RCV000208315 SCV000264090 pathogenic Primary familial hypertrophic cardiomyopathy 2015-05-21 criteria provided, single submitter clinical testing
Invitae RCV000552931 SCV000623712 likely pathogenic Hypertrophic cardiomyopathy 2019-03-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1377 of the MYH7 protein (p.Thr1377Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is absent from population databases (rs397516201, ExAC no-frequency). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27247418, 25031304, 20800588, 18409188, 16858239, 24111713, 27532257), and it has also been observed in unaffected controls (PMID: 18409188). This variant has been observed in both affected and unaffected individuals in a family with HCM (PMID: 29343710). ClinVar contains an entry for this variant (Variation ID: 42992). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000617360 SCV000739952 pathogenic Cardiovascular phenotype 2018-05-23 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Strong segregation with disease (lod >3 = >10 meioses)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000785047 SCV000923601 uncertain significance MYH7-Related Disorders 2019-01-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000785048 SCV000923602 uncertain significance not specified 2019-01-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171198 SCV001333895 likely pathogenic Cardiomyopathy 2017-11-02 criteria provided, single submitter clinical testing

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