Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001049614 | SCV001213673 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-03-23 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 66929). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 18035086, 23062543, 31317183; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 25 of the LMNA protein (p.Arg25Cys). |
| Ambry Genetics | RCV002381368 | SCV002673539 | likely pathogenic | Cardiovascular phenotype | 2021-02-22 | criteria provided, single submitter | clinical testing | The p.R25C variant (also known as c.73C>T), located in coding exon 1 of the LMNA gene, results from a C to T substitution at nucleotide position 73. The arginine at codon 25 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a family with dilated cardiomyopathy (DCM), arrhythmia, heart failure, and features of skeletal myopathy (van Tintelen JP et al. Am Heart J, 2007 Dec;154:1130-9). This variant has also been detected in DCM cohorts; however, reports may overlap (Narula N et al. J Am Coll Cardiol, 2012 Nov;60:1916-20; Jansweijer JA et al. Eur J Heart Fail, 2017 04;19:512-521; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 03;21:326-336). A different variant affecting this codon (p.R25G, c.73C>G) has also been reported in association with laminopathy-related phenotypes (Yuan WL. Chin Med J (Engl). 2009 Dec;122(23):2840-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057450 | SCV000088564 | not provided | not provided | no assertion provided | not provided |