ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504247
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2022-03-01 criteria provided, single submitter clinical testing Reported to segregate with disease in two families, but no details were provided (Brito et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last two amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Limited functional studies using human induced pluripotent stem cell-derived cardiomyocytes suggest that this variant impacts protein function (Pettinato et al., 2020); however additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 12707239, 27532257, 20439259, 23396983, 25351510, 26936621, 22857948, 20031601, 30297972, 33025817, 30975432)
Invitae RCV000627785 SCV000253859 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2024-01-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp287*) in the TNNT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TNNT2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20439259, 22857948, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177636). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000154218 SCV000256206 likely pathogenic 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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170984 SCV001333647 pathogenic Cardiomyopathy 2023-06-06 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000159326 SCV002502766 likely pathogenic not provided 2021-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002444634 SCV002677845 likely pathogenic Cardiovascular phenotype 2023-09-13 criteria provided, single submitter clinical testing The p.W287* variant (also known as c.860G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide position 860. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been detected in multiple hypertrophic cardiomyopathy (HCM) cohorts and has been reported to segregate with disease, but segregation details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Bales ND et al. Pediatr Cardiol, 2016 Jun;37:845-51; Walsh R et al. Genet. Med., 2017 02;19:192-203). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Although premature stop codons are typically deleterious in nature, loss of function of TNNT2 has not been clearly established as a mechanism of disease. This stop codon, however, occurs at the 3' terminus of TNNT2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 2 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000627785 SCV002800613 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2021-08-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453151 SCV004180469 likely pathogenic Dilated cardiomyopathy 1D 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453152 SCV004180470 likely pathogenic Cardiomyopathy, familial restrictive, 3 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000154218 SCV004180471 likely pathogenic Hypertrophic cardiomyopathy 2 2023-04-11 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000159326 SCV001928111 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000159326 SCV001951833 likely pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.