Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000818791 | SCV000959423 | uncertain significance | Charcot-Marie-Tooth disease, type 2 | 2018-12-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glycine at codon 249 of the LMNA protein (p.Arg249Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with unspecified cardiac and neuromuscular manifestations (PMID: 27884249). ClinVar contains an entry for this variant (Variation ID: 48077). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ala249 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 18551513, 20848652, 20886652, 21632249, 24508248, 26098624, 24656463, 29893365), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Laboratory for Molecular Medicine, |
RCV000041362 | SCV000065055 | uncertain significance | not specified | 2014-12-04 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |