ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.460C>T (p.Arg154Trp) (rs483352832)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612990 SCV000713432 likely pathogenic Primary dilated cardiomyopathy 2017-08-15 criteria provided, single submitter clinical testing The p.Arg144Trp variant in TNNT2 has been reported in 1 South Asian individual w ith dilated cardiomyopathy and segregated with disease in 4 affected relatives ( including 1 obligate carrier; Rani 2014). It has also been identified in 4/30672 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org/; dbSNP rs483352832). This variant was predicted to be pat hogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish i ts clinical significance, the p.Arg144Trp variant is likely pathogenic.
Invitae RCV000646060 SCV000767817 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 144 of the TNNT2 protein (p.Arg144Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs483352832, ExAC 0.006%). This variant has been reported to segregate with dilated cardiomyopathy in a single family (PMID: 24992688). ClinVar contains an entry for this variant (Variation ID: 132943). 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. 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.
Color RCV000777699 SCV000913632 uncertain significance Cardiomyopathy 2018-10-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional assays have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of these findings is not clear. This variant has been reported in four individuals from an Indian family, who were affected with dilated cardiomyopathy (PMID: 24992688). This variant has also been identified in 9/244862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology RCV000119344 SCV000154241 pathogenic Dilated cardiomyopathy 1DD no assertion criteria provided not provided Converted during submission to Pathogenic.

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