Submissions for variant NM_020631.6(PLEKHG5):c.1616C>T (p.Ala539Val)

gnomAD frequency: 0.00015  dbSNP: rs370515061

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724398	SCV000226348	uncertain significance	not provided	2017-07-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000724398	SCV000293231	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Illumina Laboratory Services, Illumina	RCV000310703	SCV000358749	uncertain significance	Neuronopathy, distal hereditary motor, 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	Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 539 of the PLEKHG5 protein (p.Ala539Val). This variant is present in population databases (rs370515061, gnomAD 0.04%). 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: 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. 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.
Ambry Genetics	RCV002399633	SCV002705805	uncertain significance	Inborn genetic diseases	2021-01-11	criteria provided, single submitter	clinical testing	The p.A539V variant (also known as c.1616C>T), located in coding exon 14 of the PLEKHG5 gene, results from a C to T substitution at nucleotide position 1616. The alanine at codon 539 is replaced by valine, 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.