ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.1783G>C (p.Glu595Gln) (rs140597591)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658112 SCV000779883 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing The E595Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E595Q variant is observed in 15/24014 (0.06%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The E595Q 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000692019 SCV000819824 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-02-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 595 of the PLEKHG5 protein (p.Glu595Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs140597591, ExAC 0.05%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. 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, 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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