ClinVar Miner

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

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Total submissions: 10
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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 pathogenic Hypertrophic cardiomyopathy 2020-10-05 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 2020-10-21 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 2020-01-09 criteria provided, single submitter clinical testing The p.A355T variant (also known as c.1063G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1063. The alanine at codon 355 is replaced by threonine, an amino acid with similar properties, and is located in the head domain. This variant has been detected in several hypertrophic cardiomyopathy (HCM) cohorts in individuals reported to have HCM, and was reported to co-segregate with disease in one small family (Richard P et al. Circulation. 2003;107(17):2227-32; Kaski JP et al. Circ Cardiovasc Genet. 2009;2(5):436-41; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; Zou Y et al. Mol Biol Rep. 2013;40(6):3969-76; Bos JM et al. Mayo Clin Proc. 2014;89(6):727-37; Walsh R et al. Genet Med. 2017;19(2):192-203; Mak TSH et al. Sci Rep. 2018;8(1):10846). 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 majority of available evidence to date, this variant is likely to be pathogenic.
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
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000470458 SCV001245076 likely pathogenic Hypertrophic cardiomyopathy 2018-06-01 criteria provided, single submitter research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000624861 SCV001442818 pathogenic Primary familial hypertrophic cardiomyopathy 2020-10-19 criteria provided, single submitter clinical testing Variant summary: MYH7 c.1063G>A (p.Ala355Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain 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 251444 control chromosomes. c.1063G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Richard_2003, Ho_2018). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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