ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.602T>C (p.Ile201Thr) (rs397516258)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035988 SCV000059640 likely pathogenic Primary dilated cardiomyopathy 2014-01-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000158747 SCV000208682 likely pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The I201T likely pathogenic variant in the MYH7 gene has been reported previously in association with DCM (Villard et al., 2005; Pugh et al., 2014; Walsh et al., 2017). Initially, I201T was reported in a female proband with DCM and her two affected family members (Villard et al., 2005). This variant has also been identified in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with disease in three affected relatives from unrelated families. This variant is not observed in large population cohorts (Lek et al., 2016). The I201T 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. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000587084 SCV000696359 likely pathogenic Cardiovascular phenotype 2016-06-20 criteria provided, single submitter clinical testing
Invitae RCV001054799 SCV001219150 pathogenic Hypertrophic cardiomyopathy 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 201 of the MYH7 protein (p.Ile201Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with dilated cardiomyopathy in a family (PMID: 15769782), and has been reported in unrelated individuals affected with this condition (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 43093). 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: "Benign"; Align-GVGD: "Class C0"). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170747 SCV001333352 likely pathogenic Cardiomyopathy 2018-03-28 criteria provided, single submitter clinical testing

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