Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000520885 | SCV000620236 | uncertain significance | not provided | 2017-08-21 | criteria provided, single submitter | clinical testing | The c.1082 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1082 T>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.1082 T>G reduces the strength of the natural splice acceptor site and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.1082 T>G on splicing in this individual is unknown. If c.1082 T>G does not alter splicing, it will result in the L361R missense change. The L361R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with PLEKHG5-related disorders (Stenson et al., 2014). |
| Invitae | RCV000800355 | SCV000940065 | uncertain significance | Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C | 2022-07-02 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 361 of the PLEKHG5 protein (p.Leu361Arg). This variant is present in population databases (rs762368406, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 451518). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
| Ambry Genetics | RCV002525205 | SCV003654995 | uncertain significance | Inborn genetic diseases | 2022-10-26 | criteria provided, single submitter | clinical testing | The c.1082T>G (p.L361R) alteration is located in exon 11 (coding exon 10) of the PLEKHG5 gene. This alteration results from a T to G substitution at nucleotide position 1082, causing the leucine (L) at amino acid position 361 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |