ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.83C>T (p.Pro28Leu)

gnomAD frequency: 0.00016  dbSNP: rs143585428
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235252 SCV000293244 uncertain significance not provided 2019-10-07 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26392352)
Invitae RCV000535663 SCV000646068 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-07-20 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the PLEKHG5 protein (p.Pro28Leu). This variant is present in population databases (rs143585428, gnomAD 0.04%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 245987). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000235252 SCV001713781 uncertain significance not provided 2020-07-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000235252 SCV001961062 uncertain significance not provided 2023-05-01 criteria provided, single submitter clinical testing PLEKHG5: PM2, PP3
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000235252 SCV002051553 uncertain significance not provided 2021-01-04 criteria provided, single submitter clinical testing PP3
Molecular Genetics, Royal Melbourne Hospital RCV002221214 SCV002498610 uncertain significance Testicular atrophy 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace proline with leucine at codon 28 of the PLEKHG5 protein (p.(Pro28Leu)). The proline residue is evolutionarily conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a moderate physicochemical difference between proline and leucine. The variant is present in a large population cohort at a frequency of 0.01% ( rs143585428, 38/281,352 alleles, 0 homozygotes in gnomAD v2.1), and has been reported as a variant of uncertain significance (ClinVar). The variant has been reported in at least three individuals with Charcot-Marie-Tooth disease with no mention of other alleles in this gene and has been identified in a single patient not affected with neuropathy in the laboratory (PMID: 26392352; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.
Ambry Genetics RCV002436058 SCV002677939 uncertain significance Inborn genetic diseases 2023-10-13 criteria provided, single submitter clinical testing The c.83C>T (p.P28L) alteration is located in exon 3 (coding exon 2) of the PLEKHG5 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the proline (P) at amino acid position 28 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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