Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152098 | SCV000200753 | uncertain significance | not specified | 2013-06-13 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The Arg205Gln v ariant in TNNT2 has not been reported in individuals with cardiomyopathy or in l arge population studies. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Two other variants at this position (Ar g205Leu and Arg205Trp) have been reported in individuals with DCM and the Arg205 Leu variant segregated in two affected relatives (Mogensen 2004, Hershberger 200 9). Functional studies for these 2 variants also suggest an impact to the protei n, though it is unknown if these in vitro assays accurately represent biological function (Mogensen 2004, Hershberger 2009). In summary, the identification of o ther variants at this position in individuals with DCM suggests that change at t his position may not be tolerated, but additional studies are needed to fully as sess the clinical significance of this variant. |
| Invitae | RCV000464711 | SCV000541931 | pathogenic | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2023-01-24 | 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. ClinVar contains an entry for this variant (Variation ID: 165539). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 26498512; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 205 of the TNNT2 protein (p.Arg205Gln). Experimental studies have shown that this missense change affects TNNT2 function (PMID: 26498512). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15542288, 15923195, 22675533, 23897817). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| Gene |
RCV000786227 | SCV001777959 | pathogenic | not provided | 2023-02-16 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate R205Q mutant thin filaments exhibited decreased calcium sensitivity (Pan et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15542288, 15923195, 23897817, 22675533, 26498512, 20031601, 35050212) |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786227 | SCV000924965 | likely pathogenic | not provided | 2016-08-03 | no assertion criteria provided | provider interpretation |