Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000036568 | SCV000060223 | uncertain significance | not specified | 2014-12-30 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg84Thr variant in TNNT2 has been identified by our laboratory in 2 Asian adults with HC M and segregated with disease in one affected family member. It was absent from large population studies, including a cohort of Asian individuals (http://exac.b roadinstitute.org). Arginine (Arg) at position 84 is conserved in mammals, but n ot in evolutionary distant species. However, the change to threonine (Thr) was p redicted to be pathogenic 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, while there is suspicion for a pathogenic r ole, the clinical significance of the p.Arg84Thr variant is uncertain. |
Gene |
RCV000159277 | SCV000209223 | uncertain significance | not provided | 2020-01-31 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27532257, 27483260, 31424582) |
Ambry Genetics | RCV000244818 | SCV000319791 | uncertain significance | Cardiovascular phenotype | 2023-06-12 | criteria provided, single submitter | clinical testing | The p.R84T variant (also known as c.251G>C), located in coding exon 7 of the TNNT2 gene, results from a G to C substitution at nucleotide position 251. The arginine at codon 84 is replaced by threonine, an amino acid with similar properties. This variant (also referred to as p.R94T, c.281G>C) co-occurred with a variant in MYBPC3 in an individual with hypertrophic cardiomyopathy (HCM) and Wolff-Parkinson-White syndrome (Kim S et al. Cardiol Young, 2018 Dec;1-4). This variant has also been detected in an additional HCM cohort, and in HCM genetic testing cohorts; however, clinical details were limited (Rubattu S et al. Int J Mol Sci, 2016 Jul;17; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Genetics and Genomics Program, |
RCV001293092 | SCV001434075 | uncertain significance | Hypertrophic cardiomyopathy | criteria provided, single submitter | research | ||
Invitae | RCV001366540 | SCV001562846 | likely pathogenic | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2023-10-25 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 84 of the TNNT2 protein (p.Arg84Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27483260, 27532257; Invitae). This variant is also known as c.281G>C (p.Arg94Thr). ClinVar contains an entry for this variant (Variation ID: 43623). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
CHEO Genetics Diagnostic Laboratory, |
RCV001798103 | SCV002042843 | uncertain significance | Cardiomyopathy | 2021-02-26 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001798103 | SCV004359948 | uncertain significance | Cardiomyopathy | 2022-05-12 | criteria provided, single submitter | clinical testing | This missense variant (also known as c.281G>C p.Arg94Thr based on a different transcript NM_001276345.2) replaces arginine with threonine at codon 84 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals affected with hypertrophic cardiomyopathy as well as in two unaffected individuals (PMID: 27483260, 27532257, 31424582). This variant has also been reported as de novo in an individual affected with hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome, who also carried a splice variant in the MYBPC3 gene (PMID: 30585570). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |