Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000529491 | SCV000657830 | pathogenic | Charcot-Marie-Tooth disease type 2 | 2022-09-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as 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: 476837). This missense change has been observed in individual(s) with autosomal dominant LMNA-related neuromuscular conditions (PMID: 28688748, 32571898; Clinvar). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 32 of the LMNA protein (p.Lys32Glu). |
| Broad Center for Mendelian Genomics, |
RCV000785916 | SCV000924493 | likely pathogenic | Congenital muscular dystrophy due to LMNA mutation | 2018-06-15 | criteria provided, single submitter | research | The heterozygous p.Lys32Glu variant was identified by our study in one individual with congenital muscular dystrophy. Trio exome analysis showed this variant to be de novo. This variant has been identified in the literature in one affected heterozygous proband (Monges et al. 2011). This variant was absent from large population studies. The Lysine (Lys) at position 32 is highly conserved in mammals and evolutionarily distant species, supporting that a change at this position may not be tolerated. Additionally, computational prediction tools suggest that this variant may impact the protein. A lab has reported this variant as likely pathogenic in Clinvar; however, the phenotype listed is Charcot-Marie-Tooth disease. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic for congenital muscular dystrophy. |