ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4135G>A (p.Ala1379Thr) (rs397516202)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000629005 SCV000059538 pathogenic Hypertrophic cardiomyopathy 2013-08-23 criteria provided, single submitter clinical testing The p.Ala1379Thr variant in MYH7 has been reported in 5 families with HCM, segre gated with disease in >15 affected relatives from 4 families (Blair 2002, Richar d 2003, Zou 2013, LMM data) and was absent from large population studies. This v ariant was predicted to be pathogenic using a computational tool clinically vali dated by our laboratory. This tool's pathogenic prediction is estimated to be co rrect 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon s egregation studies and absence from controls.
GeneDx RCV000505712 SCV000208572 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing The A1379T pathogenic variant in the MYH7 gene has been reported previously in association with HCM (Blair et al., 2002; Richard et al., 2003; Zou et al., 2013). Blair et al. (2002) reported that the A1379T variant segregated with a cardiomyopathy phenotype in 15 individuals in three unrelated families, and did not detect the variant in 200 control chromosomes. Similarly, Richard et al. (2003) reported the A1379T variant in one individual with HCM, and did not detect the variant in 200 chromosomes of healthy adult controls. Furthermore, the A1379T variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A1379T is a non-conservative amino acid substitution, it occurs at a residue is conserved across species, and it resides in the rod domain of the MYH7 gene (Richard et al., 2003). The A1379T residue may be important for thick filament assembly or for accessory protein binding; however, functional studies showed that normal accessory C10 protein binding is not affected in the presence of A1379T (Blair et al., 2002; Flashman et al., 2007).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000629005 SCV000212637 pathogenic Hypertrophic cardiomyopathy 2018-08-23 criteria provided, single submitter research MYH7 Ala1379Thr has previously been identified in multple HCM cases (Walsh R et al., 2017; Zou Y et al., 2013; Richard P et al., 2003; Blair E et al., 2002). Familial analysis by Blair E. et al. (2002) demonstrated strong segregation of this variant with disease phenotype. We have detected this variant in 4 unrelated HCM families, 3 of which were reported previously (Ingles J et al., 2017; Burns et al., 2017) and segregated to an additional 3 affected family members in one family. Furthermore, this variant is absent in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). In silico tools SIFT, MutationTaster and PolyPhen-2 predict that the variant is deleterious. More specifically, a tool designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this MYH7 Ala1379Thr variant to be "Pathogenic". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant has been identified in more than 10 unrelated probands (PS4_Strong), has strong segregation data (PP1_Strong), is rare in the general population (PM2) and in silico tools predict that it is deleterious (PP3), therefore we classify MYH7 Ala1379Thr as 'pathogenic'.
Center for Medical Genetics Ghent,University of Ghent RCV000162337 SCV000299237 likely pathogenic Familial hypertrophic cardiomyopathy 1 2016-02-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619392 SCV000737001 pathogenic Cardiovascular phenotype 2018-10-15 criteria provided, single submitter clinical testing The p.A1379T pathogenic mutation (also known as c.4135G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4135. The alanine at codon 1379 is replaced by threonine, an amino acid with some similar properties. This variant was reported to segregate with hypertrophic cardiomyopathy (HCM) or related features in multiple individuals across three HCM proband-identified families, and has also been detected in additional HCM cohorts (Blair E et al. Circ Res. 2002;90:263-9; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Richard P et al. Circulation. 2003;107:2227-32; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, p.A1379T is interpreted as a disease-causing mutation.
Invitae RCV000629005 SCV000749915 pathogenic Hypertrophic cardiomyopathy 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1379 of the MYH7 protein (p.Ala1379Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23283745, 27532257, 12707239, 27247418, 28790153) and has been shown to segregate with HCM in several families (PMID: 11861413). ClinVar contains an entry for this variant (Variation ID: 42993). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035887 SCV001337987 pathogenic Primary familial hypertrophic cardiomyopathy 2020-01-27 criteria provided, single submitter clinical testing Variant summary: MYH7 c.4135G>A (p.Ala1379Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes (gnomAD). c.4135G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Blair_2002, Ross_2017). Blair_2002 reported that this variant segregated with disease in three unrelated families and was not present in 200 control chromosomes. These data indicate that the variant is very likely to be associated with disease. At least one publication, Flashman_2007, reports this variant has no effect on interaction with C10 of cMyBP-C. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000035887 SCV000188802 likely pathogenic Primary familial hypertrophic cardiomyopathy 2013-10-16 no assertion criteria provided clinical testing

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