ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.452G>A (p.Arg151Gln) (rs730881101)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159297 SCV000209243 likely pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing A likely pathogenic variant has been identified in the TNNT2 gene. The R141Q variant has been reported in association with DCM (Rani et al., 2008; Cuenca et al., 2016); however, familial segregation information and in vitro functional studies were not included. R141Q has also been observed both independently and in conjunction with additional cardiogenetic variants among several unrelated individuals referred for cardiomyopathy testing at GeneDx. The R141Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). R141Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, a variant in the same residue (R141W) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), supporting the functional importance of this residue.In summary, R141Q in the TNNT2 gene is interpreted as a likely pathogenic variant.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768722 SCV000900092 uncertain significance Cardiomyopathy 2016-04-19 criteria provided, single submitter clinical testing
Invitae RCV000796707 SCV000936231 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 141 of the TNNT2 protein (p.Arg141Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in a single family who also carried a rare TTN variant (PMID: 26899768). ClinVar contains an entry for this variant (Variation ID: 181617). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Arg141 amino acid residue in TNNT2 have been observed in affected individuals (PMID: 11684629, 15769782, 21846512, 24992688, 26656454, 14654368, 23539503, 24367593). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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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