Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001942368 | SCV002133476 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2022-12-23 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg89 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12628721, 20160190, 23582089, 23702046, 26567375). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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: 1364307). 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). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 89 of the LMNA protein (p.Arg89Pro). |
| Victorian Clinical Genetics Services, |
RCV004785349 | SCV005400176 | uncertain significance | Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301609). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated filament domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These alternative changes, p.(Arg89Leu), p.(Arg89Cys) and p.(Arg89Gly), have been reported as pathogenic or likely pathogenic, and observed in at least ten unrelated individuals with dilated cardiomyopathy (DCM), Emery-Dreifuss muscular dystrophy or protein aggregate myopathy (ClinVar, PMID: 21922471, PMID: 27199538, PMID: 23702046, PMID: 33170376, PMID: 20160190). Another comparable variant, p.(Arg89His), has been reported as a VUS, and observed in an individual with DCM (PMID: 24503780). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |