Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000699850 | SCV000828579 | likely pathogenic | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2022-11-29 | criteria provided, single submitter | clinical testing | 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. 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. This variant disrupts the p.Arg286 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 12860912, 23785128, 26507537). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 577168). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 286 of the TNNT2 protein (p.Arg286Ser). |
Ambry Genetics | RCV002442491 | SCV002680386 | uncertain significance | Cardiovascular phenotype | 2018-04-04 | criteria provided, single submitter | clinical testing | The p.R286S variant (also known as c.856C>A), located in coding exon 15 of the TNNT2 gene, results from a C to A substitution at nucleotide position 856. The arginine at codon 286 is replaced by serine, an amino acid with dissimilar properties. Three different alterations located at the same position, p.R286C, p.R286H, and p.R286H, have been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al., Circulation 2003 Jul; 108(4):445-51; Andersen PS et al., Hum. Mutat. 2009 Mar; 30(3):363-70; Berge KE et al., Clin. Genet. 2014 Oct; 86(4):355-60; Chiou KR et al., J Cardiol 2015 Mar; 65(3):250-6; Lopes LR et al., Heart 2015 Feb; 101(4):294-301; Ripoll-Vera T et al., Rev Esp Cardiol (Engl Ed) 2016 Feb; 69(2):149-58; Richard P et al. Circulation. 2003;107(17):2227-32; Mook OR et al. J Med Genet. 2013;50(9):614-26; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600). This amino acid position is highly conserved in 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. |