ClinVar Miner

Submissions for variant NM_020631.6(PLEKHG5):c.2306C>T (p.Thr769Met)

gnomAD frequency: 0.00001  dbSNP: rs1000775772
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493291 SCV000581971 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEKHG5 gene. The T796M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T796M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T796M 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. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001070725 SCV001235993 uncertain significance Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C 2022-09-01 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 769 of the PLEKHG5 protein (p.Thr769Met). This variant is present in population databases (no rsID available, 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: 429408). 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 methionine 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 RCV002446960 SCV002734259 uncertain significance Inborn genetic diseases 2020-03-04 criteria provided, single submitter clinical testing The p.T769M variant (also known as c.2306C>T), located in coding exon 19 of the PLEKHG5 gene, results from a C to T substitution at nucleotide position 2306. The threonine at codon 769 is replaced by methionine, an amino acid with similar properties. This amino acid position is not 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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