ClinVar Miner

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

dbSNP: rs397516088
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2023-07-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 21835320, 27532257, 24704860, 24793961, 18761664, 27066507, 25351510, 20031618, 23396983, 23283745, 30022097, 31308319, 33636496, 33302605, 30847666, 32894683, 12707239, 29300372, 34542152, 31568572, 31722741, 30297972, 35626289, 35653365)
Invitae RCV000470458 SCV000546237 pathogenic Hypertrophic cardiomyopathy 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the MYH7 protein (p.Ala355Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (HCM) (PMID: 12707239, 18761664, 20031618, 21835320, 23283745, 24704860, 27247418). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620233 SCV000739919 pathogenic Cardiovascular phenotype 2021-12-17 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. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). 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; Fernlund E et al. Genes (Basel), 2020 12;11:[Epub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing 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 2021-06-18 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000225736 SCV002103254 likely pathogenic not provided 2022-06-07 criteria provided, single submitter clinical testing PP3, PM1, PM2, PS4
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV003313930 SCV004013908 pathogenic Hypertrophic cardiomyopathy 1 2023-04-12 criteria provided, single submitter clinical testing PS4, PM1, PM2, PP3, PP5
Clinical Genetics, Academic Medical Center RCV000225736 SCV001921822 likely pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000225736 SCV001928016 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000225736 SCV001951779 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000225736 SCV001975349 pathogenic not provided no assertion criteria provided clinical testing

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