ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.1738G>A (p.Glu580Lys)

gnomAD frequency: 0.00013  dbSNP: rs760122001
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236407 SCV000293569 uncertain significance not provided 2021-12-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000528786 SCV000646010 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 580 of the PLEKHG5 protein (p.Glu580Lys). This variant is present in population databases (rs760122001, gnomAD 0.02%). 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: 246143). 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. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002507 SCV001160465 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing The PLEKHG5 c.1738G>A; p.Glu580Lys variant (rs760122001), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database as uncertain (Variation ID: 246143). This variant is found in the general population with an allele frequency in non-Finnish European populations of 0.01% (19/128,754 alleles) in the Genome Aggregation Database. The glutamic acid at codon 580 is moderately conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on the available information, the clinical significance of this variant is uncertain.
Ambry Genetics RCV002401923 SCV002710224 uncertain significance Inborn genetic diseases 2022-07-22 criteria provided, single submitter clinical testing The p.E580K variant (also known as c.1738G>A), located in coding exon 15 of the PLEKHG5 gene, results from a G to A substitution at nucleotide position 1738. The glutamic acid at codon 580 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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.

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