Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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, |
RCV000154218 | SCV000256206 | likely pathogenic | Hypertrophic cardiomyopathy 2 | criteria provided, single submitter | clinical testing | ||
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000211869 | SCV000577979 | pathogenic | Primary familial hypertrophic cardiomyopathy | 2016-04-11 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV001170984 | SCV001333647 | pathogenic | Cardiomyopathy | 2023-06-06 | criteria provided, single submitter | clinical testing | |
Ai |
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, |
RCV000627785 | SCV002800613 | pathogenic | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2021-08-01 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003453151 | SCV004180469 | likely pathogenic | Dilated cardiomyopathy 1D | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003453152 | SCV004180470 | likely pathogenic | Cardiomyopathy, familial restrictive, 3 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000154218 | SCV004180471 | likely pathogenic | Hypertrophic cardiomyopathy 2 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Stanford Center for Inherited Cardiovascular Disease, |
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, |
RCV000159326 | SCV001928111 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000159326 | SCV001951833 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |