Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Blueprint Genetics | RCV000208276 | SCV000264007 | likely pathogenic | Primary dilated cardiomyopathy | 2014-12-11 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000536399 | SCV000657813 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-09-22 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 150 of the LMNA protein (p.Thr150Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 222692). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. This variant disrupts the p.Thr150 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10908904, 20848652, 24503780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Laboratory for Molecular Medicine, |
RCV000611547 | SCV000731631 | uncertain significance | not specified | 2017-05-02 | criteria provided, single submitter | clinical testing | The p.Thr150Ala variant in LMNA has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Thr150Ala variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. This variant has been reported in ClinVar (Variation ID: 222692). Of n ote, a change that the same codon (p.Thr150Pro) has been classified as likely pa thogenic (LMM data), suggesting that changes at this position may not be tolerat ed. In summary, the clinical significance of the p.Thr150Ala variant is uncertai n. |
| Ambry Genetics | RCV002327072 | SCV002635362 | uncertain significance | Cardiovascular phenotype | 2019-12-05 | criteria provided, single submitter | clinical testing | The p.T150A variant (also known as c.448A>G), located in coding exon 2 of the LMNA gene, results from an A to G substitution at nucleotide position 448. The threonine at codon 150 is replaced by alanine, an amino acid with similar properties, and is located in the central rod domain. A different variant affecting this codon (p.T150P, c.448A>C) has been reported in association with Emery-Dreifuss muscular dystrophy with cardiac arrhythmia, and in a dilated cardiomyopathy (DCM) cohort (Felice KJ et al. Neurology, 2000 Jul;55:275-80; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). An additional variant (p.T150I, c.449C>T) has also been reported in a DCM cohort (Hirtle-Lewis M et al. Clin Cardiol, 2013 Oct;36:628-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |