Submissions for variant NM_020631.6(PLEKHG5):c.1705G>A (p.Asp569Asn)

gnomAD frequency: 0.00034  dbSNP: rs200641225

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438420	SCV000514180	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in an individual with peripheral neuropathy; however, additional information was not provided (Antoniadi et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26392352)
Invitae	RCV000525392	SCV000646007	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 asparagine, which is neutral and polar, at codon 569 of the PLEKHG5 protein (p.Asp569Asn). This variant is present in population databases (rs200641225, gnomAD 0.06%). This missense change has been observed in individual(s) with inherited peripheral neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 378377). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV001099856	SCV001256345	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000438420	SCV001473095	uncertain significance	not provided	2020-04-03	criteria provided, single submitter	clinical testing	The PLEKHG5 c.1705G>A; p.Asp569Asn variant (rs200641225) is reported in the literature in an individual affected with inherited peripheral neuopathy (Antoniadi 2015). This variant is reported in ClinVar (Variation ID: 378377), and is found in the general population with an overall allele frequency of 0.030% (85/282250 alleles) in the Genome Aggregation Database. The aspartic acid at codon 569 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Asp569Asn variant is uncertain at this time. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84.
Ambry Genetics	RCV002411299	SCV002715808	uncertain significance	Inborn genetic diseases	2022-06-08	criteria provided, single submitter	clinical testing	The p.D569N variant (also known as c.1705G>A), located in coding exon 15 of the PLEKHG5 gene, results from a G to A substitution at nucleotide position 1705. The aspartic acid at codon 569 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been seen in an individual with features of Charcot-Marie-Tooth disease type 2 (Antoniadi T et al. BMC Med. Genet., 2015 Sep;16:84). 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.
Baylor Genetics	RCV001099856	SCV003835558	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 4	2022-09-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000438420	SCV004227734	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	BP4