ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.1082T>G (p.Leu361Arg) (rs762368406)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 361 of the PLEKHG5 protein (p.Leu361Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs762368406, ExAC 0.005%). This variant has not been reported in the literature in individuals 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.

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