Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV002467496 | SCV002764409 | uncertain significance | Familial partial lipodystrophy, Dunnigan type | 2021-10-18 | criteria provided, single submitter | clinical testing | The heterozygous c.1586C>T (p.Ala529Val) variant identified in the LMNA gene substitutes a very well conserved Alanine for Valine at amino acid529/664 (exon 9/12). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score: 1.0328) and Benign (REVEL; score: 0.492) to the function of the canonical transcript. This variant is reported in ClinVar as Pathogenic (VarID:14513) and has been reported at the homozygous state in 4 affected individual (3 families) in the literature with mandibuloacral dysplasia (MAD) [PMID: 15998779, 27100822]. Heterozygous carriers have been reported without phenotypic abnormalities of MAD but two of them had diabetes mellitus. Hyperglycemia in heterozygous carriers might be related to the heterozygous p.Ala529Val variant in the LMNA gene, but these data have to be confirmed. Given the lack of compelling evidence for its pathogenicity in metabaloic disorders, the c.1586C>T, p.Ala529Val variant identified in the LMNA gene is reported as a Variant of Uncertain Significance. |
| Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, |
RCV003234906 | SCV003932860 | likely pathogenic | Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 2023-06-21 | criteria provided, single submitter | research | |
| OMIM | RCV000015608 | SCV000035873 | pathogenic | Mandibuloacral dysplasia with type A lipodystrophy | 2005-09-01 | no assertion criteria provided | literature only | |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057332 | SCV000088445 | not provided | not provided | no assertion provided | not provided | ||
| Ambry Genetics | RCV002399329 | SCV002705213 | uncertain significance | Cardiovascular phenotype | 2021-12-21 | flagged submission | clinical testing | The p.A529V pathogenic mutation (also known as c.1586C>T), located in coding exon 9 of the LMNA gene, results from a C to T substitution at nucleotide position 1586. The alanine at codon 529 is replaced by valine, an amino acid with similar properties. This variant has been reported in homozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD); heterozygous carrier family members were reported to be unaffected with MAD or other laminopathy-related phenotypes (Cogulu O et al. Am J Med Genet A, 2003 Jun;119A:391-2; Garg A et al. J Clin Endocrinol Metab, 2005 Sep;90:5259-64; Ozer L et al. Clin Dysmorphol, 2016 Jul;25:91-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear. |