ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.472C>T (p.Arg158Trp) (rs730881123)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159339 SCV000209285 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing The R148W variant of uncertain significance in the TNNT2 gene has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has previously been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The R148W 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000697959 SCV000826594 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 148 of the TNNT2 protein (p.Arg148Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 181643). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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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