ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.274G>A (p.Val92Ile) (rs371516662)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236807 SCV000293040 uncertain significance not provided 2015-07-23 criteria provided, single submitter clinical testing The V92I variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The V92I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V92I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000645436 SCV000767181 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 92 of the PLEKHG5 protein (p.Val92Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs371516662, ExAC 0.009%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 245867). 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: "Benign"; 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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