Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV001330500 | SCV001522191 | uncertain significance | Hutchinson-Gilford syndrome | 2019-12-03 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Invitae | RCV001367762 | SCV001564125 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the LMNA protein (p.Ile63Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1029259). 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 with a positive predictive value of 95%. This variant disrupts the p.Ile63 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 10939567, 12467752, 28688748), 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. |
| Phosphorus, |
RCV001823769 | SCV002073403 | uncertain significance | not specified | 2022-01-18 | criteria provided, single submitter | clinical testing | This missense variant results in an amino acid substitution of Isoleucine with Leucine at codon 63 of the LMNA gene (transcript: NM_170707.3). This variant has an entry in ClinVar (1029259) NM_170707.4(LMNA):c.187A>C (p.Ile63Leu). This variant is very rare and has not occurred in population databases. This position is conserved. In silico functional algorithms predict this variant to be benign (PolyPhen) and tolerated (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has not occurred in the literature in association with disease; however, another variant associated with Emery Dreifuss muscular dystrophy, I63N, has been detected and predicted to be in a residue that may be clinically significant for filament assembly (PMID: 12467752). Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002499650 | SCV002777420 | uncertain significance | Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2 | 2021-12-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003365335 | SCV004055117 | uncertain significance | Cardiovascular phenotype | 2023-07-03 | criteria provided, single submitter | clinical testing | The p.I63L variant (also known as c.187A>C), located in coding exon 1 of the LMNA gene, results from an A to C substitution at nucleotide position 187. The isoleucine at codon 63 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |