Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000146262 | SCV000193525 | likely pathogenic | Lipodystrophy | 2014-06-24 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001234965 | SCV001407628 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2022-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 300 of the LMNA protein (p.Asp300Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 19095983, 25327215, 29047356, 32548202). ClinVar contains an entry for this variant (Variation ID: 66952). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects LMNA function (PMID: 30696354). This variant disrupts the p.Asp300 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 23666920, 30123186, 32954377), which suggests that this may be a clinically significant amino acid residue. 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. |
| New York Genome Center | RCV003227631 | SCV003925452 | pathogenic | Dilated cardiomyopathy 1A | 2022-04-08 | criteria provided, single submitter | clinical testing | The c.898G>A variant in LMNA has previously been reported in a heterozygous state in over ten individuals with variable features of laminopathies such as lipodystrophy, progeria, diabetes, non-alcoholic fatty liver disease, and early onset coronary artery disease and cardiomyopathy [PMID:19095983, 28938416,29047356, 32413188, 32548202, 32901917, 33502018], and it has been deposited in ClinVar [ClinVar ID: 66952] as Variant of Uncertain Significance for Charcot-Marie-Tooth disease, type 2 and Likely Pathogenic for Lipodystrophy. The c.898G>A variant is absent from population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.898G>A variant is located inexon 5 of this 12-exon gene, and predicted to replace an evolutionarily conserved aspartate amino acid with asparagine at position 300 within the intermediate filament domain of the encoded protein [UniProtKB ID: P02545]. In silico predictions are moderately in favor of damaging effect for p.(Asp300Asn) [CADD v1.6 = 29.9,REVEL = 0.606]. Cardiac myocytes of mice models carrying p.Asp300Asn allele were shown to result in myocardial fibrosis, apoptosis, and cardiac dysfunction [PMID:30696354]. Variants affecting the same residue (p.(Asp300Gly) and p.(Asp300His)) have also been reported in literature in individuals with laminopathies [PMID:22991222, 23666920, 25327215, 30123186, 32954377]. Based on available evidence this c.898G>A p.(Asp300Asn) variant identified in LMNA in is classified as Pathogenic. |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057481 | SCV000088595 | not provided | not provided | no assertion provided | not provided |