ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.881G>A (p.Trp294Ter) (rs727504247)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824774 SCV000203872 pathogenic Hypertrophic cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing The p.Trp287X variant in TNNT2 has been identified in >20 individuals with HCM a nd segregated with disease in 7 affected relatives from 6 families (Richard 2003 , Gandjbakhch 2010, Brito 2012, D. Brito pers comm, GeneDx pers comm; LMM data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). In addition, the p.Trp278X variant has been identified in 1/32874 Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org/ dbSNP rs727504247). This nonsens e variant leads to a premature termination codon at position 287. This alteratio n occurs within the last exon and may therefore escape nonsense mediated decay ( NMD), resulting in a truncated protein that is lacking the last 2 amino acids. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon case observations and segregation s tudies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PM4_Supporting.
GeneDx RCV000159326 SCV000209272 likely pathogenic not provided 2018-09-28 criteria provided, single submitter clinical testing The W287X likely pathogenic variant has been reported previously in several unrelated individuals diagnosed with HCM (Richard et al., 2003; Hershberger et al., 2009; Gandjbakhch et al., 2010; Brito et al., 2012; Walsh et al., 2017). Brito et al. (2012) reported that W287X segregated with disease in two unrelated families with HCM. However, W287X has also been reported in association with HCM in individuals who also harbored other gene variants (Lopes et al., 2013; Bales et al., 2016). In addition this variant is classified as pathogenic by other clinical laboratories in ClinVar (SCV000203872.3, SCV000253859.3; Landrum et al., 2016). Although W287X has been identified in multiple other individuals referred for HCM genetic testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. Furthermore, this variant is not observed in large population cohorts (Lek et al., 2016). Lastly, Although W287X replaces the penultimate residue of the troponin T molecule and is predicted to cause protein truncation with the loss of the last 2 amino acid residues of the protein, 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. In summary, W287X in the TNNT2 gene is interpreted as a likely pathogenic variant.
Invitae RCV000627785 SCV000253859 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-11 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 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 23396983) and was reported to segregate with the phenotype in several families (PMID: 22857948, 20439259). ClinVar contains an entry for this variant (Variation ID: 177636). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000154218 SCV000256206 likely pathogenic Familial hypertrophic cardiomyopathy 2 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000211869 SCV000577979 pathogenic Primary familial hypertrophic cardiomyopathy 2016-04-11 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159326 SCV000280537 likely pathogenic not provided 2012-01-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp287Stop (c.860 G>A, W287X) in TNNT2. Given strong case data, absence in controls, and segregation in multiple families, (all reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 14 unrelated cases of HCM (not including the patient's family). There is weak segregation data in at least 6 families. Brito et al (2012) observed the variant in 3 of 77 unrelated individuals with HCM in their Portuguese cohort. Two of these patients have affected relatives and the authors note the variant segregated with disease however they do not provide details on the number of affected relatives with the variant. Richard et al (2003) observed the variant in 2 unrelated patients in their cohort of 197 HCM patients from France (likely redundant with Gandjbackhch et al 2010 from the same group). Bill McKenna's group observed the variant in 1 out of 223 HCM patients from their UK cohort (Lopes et al 2013). GeneDx shared they've seen it in one patient tested for HCM (presumably this family) and two tested with a DCM panel. I have requested phenotype and ancestry data. A genetic testing lab shared with us that they have seen the variant in multiple patients with HCM with segregation in some families. Of note, most of these cases were Portuguese. The variant affects one of the last residues in the protein, though it is a bit unclear how far to the end (the labs and papers conflict). The testing lab reports we have do not provide the transcript they used. Per another source, this affects the second last residue of the protein, creating a stop codon where there would normally be a tryptohan. It would lead to loss of the last two amino acids. Unlike nonsense variants that occur earlier in the amino acid sequence this variant would most likely not lead to nonsense-mediate mRNA decay. Notably, the end of the protein is highly conserved across mammals In total the variant has not been seen in ~6400 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6300 Caucasian and African American individuals (as of February 18th, 2014). It is also not listed in dbSNP. The variant was not observed in 100 healthy adults analyzed by Richard et al (2003). Unfortunately there are not any Portuguese controls available.

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