ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.1616C>T (p.Ala539Val) (rs370515061)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724398 SCV000226348 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
GeneDx RCV000724398 SCV000293231 uncertain significance not provided 2015-10-07 criteria provided, single submitter clinical testing The A539V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A539V variant was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The A539V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species. Missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with PLEKHG5-related disorders (Stenson et al., 2014). However, 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.
Illumina Clinical Services Laboratory,Illumina RCV000310703 SCV000358749 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000645414 SCV000767159 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 539 of the PLEKHG5 protein (p.Ala539Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs370515061, ExAC 0.06%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 194553). 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, but 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001707 SCV001159284 uncertain significance not specified 2019-03-13 criteria provided, single submitter clinical testing The p.Ala539Val variant (rs370515061) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.04 percent (identified on 45 out of 100,098 chromosomes) and has been reported to the ClinVar database (Variation ID: 194553). The alanine at position 539 is moderately conserved and computational analyses of the effects of the p.Ala539Val variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ala539Val variant with certainty.

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