Submissions for variant NM_020631.6(PLEKHG5):c.719A>G (p.Asp240Gly)

gnomAD frequency: 0.00041  dbSNP: rs199794578

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724237	SCV000232768	uncertain significance	not provided	2014-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724237	SCV000279364	likely benign	not provided	2021-05-07	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
Invitae	RCV000546292	SCV000646063	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 240 of the PLEKHG5 protein (p.Asp240Gly). This variant is present in population databases (rs199794578, gnomAD 0.08%). 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: 198894). 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.
Illumina Laboratory Services, Illumina	RCV001098160	SCV001254508	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724237	SCV001713778	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372106	SCV002672319	uncertain significance	Inborn genetic diseases	2021-12-13	criteria provided, single submitter	clinical testing	The p.D240G variant (also known as c.719A>G), located in coding exon 7 of the PLEKHG5 gene, results from an A to G substitution at nucleotide position 719. The aspartic acid at codon 240 is replaced by glycine, 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.
Clinical Genetics, Academic Medical Center	RCV000724237	SCV001920949	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724237	SCV001964041	uncertain significance	not provided		no assertion criteria provided	clinical testing