ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.797A>G (p.Tyr266Cys) (rs1553280112)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521498 SCV000618742 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNT2 gene. The Y259C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y259C 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. 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. Finally, at least one splice prediction algorithm suggests that the Y259C variant may create a cryptic splice donor site at intron 14, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae RCV000532750 SCV000646912 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 259 of the TNNT2 protein (p.Tyr259Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. 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: 450191). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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