ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.644G>A (p.Arg215Gln) (rs121964860)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized 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 Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 205 of the TNNT2 protein (p.Arg205Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in a single family (PMID: 26498512), and it has been observed in an individual with clinical features of this condition (Invitae). ClinVar contains an entry for this variant (Variation ID: 165539). Experimental studies have shown that this missense change affects Ca2+ sensitivity (PMID: 26498512). This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23897817, 15542288, 15923195, 22675533), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786227 SCV000924965 likely pathogenic not provided 2016-08-03 no assertion criteria provided provider interpretation

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