Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000242724 | SCV000320443 | likely pathogenic | Cardiovascular phenotype | 2017-03-01 | criteria provided, single submitter | clinical testing | The p.D84N variant (also known as c.250G>A), located in coding exon 3 of the TPM1 gene, results from a G to A substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by asparagine, an amino acid with highly similar properties. In one family, this variant was observed to co-segregate with dilated cardiomyopathy (DCM) (van de Meerakker JB et al. Biochim Biophys Acta. 2013;1833(4):833-9). In the same study, in vitro functional analysis indicated this variant would interfere with the electrostatic interaction between tropomyosin and the actin molecule in the presence of Ca2+ resulting in weakened binding capacity. Similar findings were observed in other in vitro functional studies in which disturbance of the electrostatic interaction would lead to decreased Ca2+ sensitivity and therefore a hypotonic response and reduced cardiac contractile function (Orzechowski M et al. Arch Biochem Biophys. 2014;564:89-99; Gupte TM et al. J Biol Chem. 2015;290(11):7003-15). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV002518731 | SCV003441690 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-09-06 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23147248, 29447731, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264474). 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: 23147248, 25241052, 25548289). 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. This variant is present in population databases (rs754664923, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 84 of the TPM1 protein (p.Asp84Asn). |
Clinical Genetics, |
RCV001699094 | SCV001922419 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001699094 | SCV001953677 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001699094 | SCV001968484 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |