ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.655G>A (p.Glu219Lys)

gnomAD frequency: 0.00001  dbSNP: rs774845320
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489343 SCV000576755 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing The E219K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E219K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. However, this 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV001343270 SCV001537239 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-07-19 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 219 of the PLEKHG5 protein (p.Glu219Lys). This variant is present in population databases (rs774845320, gnomAD 0.004%). 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: 426342). 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: "Tolerated"; PolyPhen-2: "Possibly 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 RCV002367663 SCV002663483 uncertain significance Inborn genetic diseases 2022-05-04 criteria provided, single submitter clinical testing The c.655G>A (p.E219K) alteration is located in exon 8 (coding exon 7) of the PLEKHG5 gene. This alteration results from a G to A substitution at nucleotide position 655, causing the glutamic acid (E) at amino acid position 219 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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