Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236639 | SCV000292848 | uncertain significance | not provided | 2015-04-24 | criteria provided, single submitter | clinical testing | The R386S variant has not been published as a pathogenic variant or been reported as a benign polymorphism to our knowledge. The R386S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the R386S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties; this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Located in the tail region of the LMNA gene, another missense variant in the same residue (R386M) and missense variants in nearby residues (G382V, G382G, L387V, R388C, R388H) have been reported in the HGMD in association with LMNA-related disorders (Stenson et al., 2009), supporting the functional importance of this region of the protein. |
| Invitae | RCV002518430 | SCV003333438 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2022-03-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 386 of the LMNA protein (p.Arg386Ser). 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. This variant disrupts the p.Arg386 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23427149; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 245758). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). |