ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5561C>T (p.Thr1854Met) (rs372381770)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154324 SCV000203986 uncertain significance not specified 2020-04-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr1854Met variant in MYH7 has been reported in >6 individuals with HCM (Van Dreist 2004 PMID: 15358028; reported incorrectly as p.Thr1834Met, Page 2012 PMID:22267749, Zou 2013 PMID:23283745, Chiou 2015 PMID:25086479, Walsh 2017 PMID:27532257, Wang 2019 PMID:31638223, LMM data) and by other clinical laboratories in ClinVar (Variation ID 161320). It has also been identified in 7/126622 European chromosomes by gnomAD ( Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Thr1854Met variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3.
GeneDx RCV000158710 SCV000208645 pathogenic not provided 2013-08-07 criteria provided, single submitter clinical testing p.Thr1854Met (ACG>ATG): c.5561 C>T in exon 38 of the MYH7 gene (NM_000257.2). The Thr1854Met mutation in the MYH7 gene was reported in one individual diagnosed with HCM and not present in 400 normal chromosomes of African American and Caucasian backgrounds. (Of note, due to an error in the Van Driest et al. cited report, the mutation is denoted T1834M) (Van Driest S et al., 2004). In addition, Thr1854Met was identified in three individuals diagnosed with HCM from one family, two of whom were also heterozygous for a variant in the MYBPC3 gene (IVS14-13 G>A) (Page S et al., 2012). Furthermore, Thr1854Met was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thr1854Met results in a non-conservative amino acid substitution of a hydrophilic, basic Threonine residue with a hydrophobic Methionine. Mutations in nearby residues (Lys1848Thr, Arg1858Met, Arg1863Gln) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The variant is found in HCM panel(s).
Invitae RCV000457760 SCV000546198 likely pathogenic Hypertrophic cardiomyopathy 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1854 of the MYH7 protein (p.Thr1854Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs372381770, ExAC 0.006%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 25086479, 23283745, Invitae). ClinVar contains an entry for this variant (Variation ID: 161320). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Blueprint Genetics RCV000158710 SCV000927530 uncertain significance not provided 2018-02-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158710 SCV001149157 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170482 SCV001333063 uncertain significance Cardiomyopathy 2018-09-18 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148695 SCV000190424 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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