ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.460C>T (p.Arg154Trp) (rs483352832)

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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 RCV000612990 SCV000713432 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg144Trp variant in TNNT2 has been reported in 1 individual with dilated cardiomyopathy and segregated with disease in 4 affected relatives, including 1 obligate carrier (Rani 2014). It has also been identified in 4/30504 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #132943). An in vitro functional study suggests that this variant may disrupt troponin binding (Gangadharan 2017) and computational prediction tools suggest that it may impact the protein, though this information is not predictive enough to determine pathogenicity.In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PS3_Supporting, PP1, PP3.
Invitae RCV000646060 SCV000767817 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-09-24 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). Experimental studies have shown that this variant affects TNNT2 protein function (PMID: 28973951). 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 Health, Inc RCV000777699 SCV000913632 uncertain significance Cardiomyopathy 2020-02-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777699 SCV001333852 likely pathogenic Cardiomyopathy 2018-08-20 criteria provided, single submitter clinical testing
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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