ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.997C>T (p.Arg333Trp)

dbSNP: rs148232621
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413441 SCV000492013 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEKHG5 gene. The R333W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R333W variant is observed in 10/54458 (0.0001%) alleles from individuals of European (Non-Finnish) background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R333W 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably 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 RCV000552251 SCV000646075 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the PLEKHG5 protein (p.Arg333Trp). This variant is present in population databases (rs148232621, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 373421). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Ambry Genetics RCV002379271 SCV002688904 uncertain significance Inborn genetic diseases 2020-05-13 criteria provided, single submitter clinical testing The p.R333W variant (also known as c.997C>T), located in coding exon 9 of the PLEKHG5 gene, results from a C to T substitution at nucleotide position 997. The arginine at codon 333 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV003409580 SCV004128079 uncertain significance not provided 2023-08-01 criteria provided, single submitter clinical testing PLEKHG5: PM2

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