ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.719A>G (p.Asp240Gly) (rs199794578)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724237 SCV000232768 uncertain significance not provided 2014-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000724237 SCV000279364 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEKHG5 gene. The D240G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D240G variant is observed in 11/11,186 (0.1%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D240G 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 where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000546292 SCV000646063 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 240 of the PLEKHG5 protein (p.Asp240Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs199794578, ExAC 0.1%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 198894). 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: "Tolerated"; 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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