ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.518G>A (p.Arg173Gln) (rs142378760)

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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 RCV000724523 SCV000232290 uncertain significance not provided 2015-02-13 criteria provided, single submitter clinical testing
GeneDx RCV000236863 SCV000292664 uncertain significance not specified 2016-02-25 criteria provided, single submitter clinical testing The R173Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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 R173Q 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 Arginine 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 RCV000529715 SCV000646056 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 173 of the PLEKHG5 protein (p.Arg173Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142378760, ExAC 0.01%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 198580). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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