ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.718G>A (p.Asp240Asn) (rs765882140)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489626 SCV000577542 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEKHG5 gene. The D240N variant has been previously reported as a variant of uncertain significance in a patient with CMT2 (Lupo et al., 2016). The D240N 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). The D240N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001051945 SCV001216130 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 240 of the PLEKHG5 protein (p.Asp240Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs765882140, ExAC 0.02%). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 26752306). ClinVar contains an entry for this variant (Variation ID: 426957). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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