Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000041362 | SCV000065055 | likely pathogenic | Laminopathy | 2019-03-18 | criteria provided, single submitter | clinical testing | The Arg249Gly variant in LMNA has been identified by our laboratory in one individual with conduction system disease and a family history of myopathy and sudden cardiac death. This variant was absent from large population studies. Two additional variants involving this codon (p.Arg249Gln and p.Arg249Trp) have been reported in greater than 20 individuals (with multiple de novo occurrences) with an LMNA-associated myopathy, including Emery-Dreifuss and limb-girdle muscular dystrophies, and have been classified as pathogenic by multiple clinical laboratories. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LMNA-associated myopathy. ACMG/AMP Criteria applied: PM5_Strong, PM2, PP3. |
| Labcorp Genetics |
RCV000818791 | SCV000959423 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2024-05-20 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 249 of the LMNA protein (p.Arg249Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 27884249; Invitae). ClinVar contains an entry for this variant (Variation ID: 48077). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala249 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18551513, 20848652, 20886652, 21632249, 24508248, 24656463, 26098624, 29893365). 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. |