ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.445C>T (p.Arg149Cys) (rs397516465)

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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 RCV000036588 SCV000060243 uncertain significance not specified 2015-03-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg139Cys variant in TNNT2 has been identified by our laboratory in 1 African infant with DCM and segregated with disease in 2 affected relatives (a parent and sibling). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical si gnificance of the p.Arg139Cys variant is uncertain.
GeneDx RCV000505718 SCV000209240 likely pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing The R139C likely pathogenic variant in the TNNT2 gene has been previously reported in at least two individuals with DCM (Chami et al., 2014; Pugh et al., 2014; Walsh et al., 2017). Additionally, although this variant is classified in ClinVar as a variant of uncertain significance by another clinical laboratory, this laboratory reports R139C segregated with disease in two affected relatives from one family (ClinVar SCV000060243.4; Landrum et al., 2016). The R139C 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a likely pathogenic variant at the same residue (R139H) has also been previously reported in association with DCM (Morales et al., 2010), supporting the functional significance of this residue. Finally, the R139C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845416 SCV000987484 likely pathogenic Primary familial dilated cardiomyopathy criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171164 SCV001333853 likely pathogenic Cardiomyopathy 2018-05-16 criteria provided, single submitter clinical testing
Invitae RCV001222522 SCV001394622 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-06-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 139 of the TNNT2 protein (p.Arg139Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 25448463, 27532257). ClinVar contains an entry for this variant (Variation ID: 43640). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg139 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20973921, 27532257, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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