ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.83C>T (p.Pro28Leu) (rs143585428)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235252 SCV000293244 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing A second variant of uncertain significance has been identified in the PLEKHG5 gene. The P28L variant has been reported as a variant of unknown clinical significance in three individuals with CMT; however, limited further information was provided and it was not reported whether a second PLEKHG5 variant was identified in trans in these individuals (Antoniadi et al., 2015). The P28L variant is observed in 13/34416 (0.04%) alleles from individuals of Latino background and in 37/276138 (0.01%) alleles globally in large population cohorts (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000535663 SCV000646068 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 28 of the PLEKHG5 protein (p.Pro28Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs143585428, ExAC 0.06%). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 245987). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on PLEKHG5 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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