ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.541G>A (p.Ala181Thr) (rs527341275)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727189 SCV000706489 uncertain significance not provided 2017-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000727189 SCV000292785 uncertain significance not provided 2018-02-07 criteria provided, single submitter clinical testing The A181T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The 1000 Genomes Project reports A181T was observed in 4/206 (1.94%) alleles from individuals of Gujarati Indian background in Texas and in 1/192 (0.52%) alleles from individuals of African Caribbean background in Barbados. The A181T 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 across species, and Threonine is seen at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000700354 SCV000829106 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 181 of the PLEKHG5 protein (p.Ala181Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs527341275, ExAC 0.1%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 245720). 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 threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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