ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.2609C>T (p.Pro870Leu)

gnomAD frequency: 0.00002  dbSNP: rs772693344
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236354 SCV000293958 uncertain significance not provided 2022-01-31 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001221063 SCV001393086 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-05-22 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 870 of the PLEKHG5 protein (p.Pro870Leu). This variant is present in population databases (rs772693344, gnomAD 0.01%). 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: 246413). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV002436063 SCV002745217 uncertain significance Inborn genetic diseases 2019-10-31 criteria provided, single submitter clinical testing The p.P870L variant (also known as c.2609C>T), located in coding exon 19 of the PLEKHG5 gene, results from a C to T substitution at nucleotide position 2609. The proline at codon 870 is replaced by leucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM RCV003338481 SCV004047709 uncertain significance Charcot-Marie-Tooth disease recessive intermediate C criteria provided, single submitter clinical testing The missense c.2609C>T (p.Pro870Leu) variant in PLEKHG5 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The variant is observed in 0.003% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Pro at position 870 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance.

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