ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.882G>A (p.Trp294Ter) (rs730881116)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159328 SCV000209274 likely pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing The W287X (c.861 G>A) likely pathogenic variant in the TNNT2 gene has not been reported as a pathogenic or benign to our knowledge. However, a different nucleotide change, c.860 G>A, that results in the same nonsense W287X variant, has been reported previously in several unrelated individuals diagnosed with HCM (Richard et al., 2003; Hershberger et al., 2009; Lopes et al., 2013 Brito et al., 2012; Walsh et al., 2017). The W287X variant has also been reported in individuals with HCM, but the nucleotide change was not specified (Gandjbakhch et al., 2010; Bales et al., 2016). The W287X variant is within the last exon of TNNT2 and is predicted to cause protein truncation with loss of the last two amino acid residues of the protein. Nevertheless, only one other nonsense variant in the TNNT2 gene has been reported in the Human Gene Mutation Database occurring upstream, and the clinical significance of this variant is currently unknown. Thus, in the absence of functional studies, the consequences of this variant cannot be precisely determined. Lastly, the W287X (c.861 G>A) variant is not observed in large population cohorts (Lek et al., 2016). In summary, W287X in the TNNT2 gene is interpreted as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000586854 SCV000697570 pathogenic Cardiovascular phenotype 2017-01-09 criteria provided, single submitter clinical testing Variant summary: The TNNT2 c.861G>A (p.Trp287X) variant results in a premature termination codon, predicted to cause a truncated or absent TNNT2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP, or publications) and has been reported in multiple affected individuals. In addition, a clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000646064 SCV000767821 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-11-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TNNT2 gene (p.Trp287*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 2 amino acids of the TNNT2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals individuals affected with hypertrophic cardiomyopathy (PMID: 12707239). ClinVar contains an entry for this variant (Variation ID: 181636). A different variant (c.861G>A) giving rise to the same protein effect observed here (p.Trp287*) has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983, 22857948, 20439259), indicating that the last 2 residues of the TNNT2 protein may be critical for 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606000 SCV000713356 likely pathogenic Hypertrophic cardiomyopathy 2017-11-02 criteria provided, single submitter clinical testing The p.Trp287X (c.861G>A) variant in TNNT2 has not been previously reported in th e literature or in large population studies. However, another variant (c.860G>A) that leads to the same amino acid change (p.Trp287X) has been identified in >20 individuals with HCM and segregated with disease in 7 affected relatives from 6 families (Richard 2003, Gandjbakhch 2010, Brito 2012, Lopez 2013, D. Brito pers comm, GeneDx pers comm; LMM unpublished data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). This nonsense variant leads to a premature termination codon at posi tion 287. This alteration occurs within the last exon and may therefore escape n onsense mediated decay (NMD), resulting in a truncated protein that is lacking t he last 2 amino acids. In summary, although additional studies are required to f ully establish its clinical significance, the p.Trp287X variant is likely pathog enic. ACMG/AMP Criteria applied: PS1, PM4, PM2 (Richards 2015).

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