Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000036322 | SCV000059974 | likely pathogenic | Primary dilated cardiomyopathy | 2014-11-11 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Invitae | RCV001852573 | SCV002315283 | likely pathogenic | Hypertrophic cardiomyopathy | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 92 of the TPM1 protein (p.Ile92Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20215591, 21483645, 27532257, 33906374; Invitae). ClinVar contains an entry for this variant (Variation ID: 31891). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 29496559). 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. |
| Ambry Genetics | RCV002433467 | SCV002752017 | uncertain significance | Cardiovascular phenotype | 2023-09-06 | criteria provided, single submitter | clinical testing | The p.I92T variant (also known as c.275T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 275. The isoleucine at codon 92 is replaced by threonine, an amino acid with similar properties. This variant has been detected in identical twins with pediatric-onset dilated cardiomyopathy (DCM), and was also detected in relatives reported to have DCM (Hershberger RE et al. Circ Cardiovasc Genet, 2010 Apr;3:155-61;Rampersaud E et al. Prog. Pediatr. Cardiol., 2011 Jan;31:39-47). This variant has also been reported in cohorts referred for DCM genetic testing; however, details were limited and reports may overlap (Walsh R et al. Genet. Med., 2017 02;19:192-203; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). One study reported this variant may impact protein function (liwinska M et al. Biochim Biophys Acta Proteins Proteom, 2018 Apr;1866:558-568). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Leiden Muscular Dystrophy |
RCV000024587 | SCV000045896 | not provided | not provided | 2012-04-15 | no assertion provided | curation |