ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1063G>A (p.Ala355Thr) (rs397516088)

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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 RCV000470458 SCV000059347 likely pathogenic Hypertrophic cardiomyopathy 2018-03-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000225736 SCV000208717 likely pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing The A355T likely pathogenic variant in the MYH7 gene has been reported previously in association with HCM (Richard et al., 2003; Kaski et al., 2009; Olivotto et al., 2011; Zou et al., 2013; Lopes et al., 2015; Ceyhan-Birsoy et al., 2016; Walsh et al., 2017). Richard et al. (2003) reported that A355T, along with V896M in the MYBPC3 gene, segregated with HCM in three individuals in one family, and that A355T was not present in 200 chromosomes from healthy control individuals. Subsequent studies reported V896M as a benign variant, providing further evidence for the pathogenicity of A355T in the MYH7 gene (Morner et al., 2003; Van Driest et al., 2004). Additional studies by Kaski et al. (2009), Olivotto et al. (2011), and Zou et al. (2013) reported A355T in at least three other unrelated individuals with HCM. Moreover, A355T has been identified in multiple other unrelated individuals tested for HCM at GeneDx and appears to segregate with disease in several of these families. Furthermore, A355T is not observed in large population cohorts (Lek et al., 2016). The A355T 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, to our knowledge no studies have been performed to determine the functional effect of the A355T variant.
Invitae RCV000470458 SCV000546237 pathogenic Hypertrophic cardiomyopathy 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 355 of the MYH7 protein (p.Ala355Thr). 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 numerous individuals affected with hypertrophic cardiomyopathy (HCM) (PMID:27247418, 23283745, 21835320, 18761664, 20031618, 24704860) and has been shown to segregate with HCM in an affected family (PMID: 12707239). ClinVar contains an entry for this variant (Variation ID: 42820). 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, this variant is absent from population databases, but has been reported in a family and in numerous affected individuals. For these reasons it has been classified as Pathogenic.
Ambry Genetics RCV000620233 SCV000739919 likely pathogenic Cardiovascular phenotype 2018-11-14 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
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624861 SCV000740377 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-04-18 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769462 SCV000900856 likely pathogenic Cardiomyopathy 2017-01-04 criteria provided, single submitter clinical testing
Klaassen Lab,Charite University Medicine Berlin RCV000624861 SCV000995870 pathogenic Primary familial hypertrophic cardiomyopathy 2019-07-03 criteria provided, single submitter research
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000470458 SCV001142720 pathogenic Hypertrophic cardiomyopathy 2020-01-10 criteria provided, single submitter clinical testing

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