Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000493099 | SCV000583082 | likely pathogenic | not provided | 2017-05-25 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the LMNA gene. The A147P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A147P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A147P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Furthermore, missense variants in nearby residues (S143P/F, E145K, T150P/I) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV001060974 | SCV001225696 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2019-03-23 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 430306). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 147 of the LMNA protein (p.Ala147Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |