ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.1705G>A (p.Asp569Asn) (rs200641225)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438420 SCV000514180 uncertain significance not provided 2020-03-19 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; This variant is associated with the following publications: (PMID: 26392352)
Invitae RCV000525392 SCV000646007 uncertain significance Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2020-06-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 569 of the PLEKHG5 protein (p.Asp569Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200641225, ExAC 0.06%). This variant has been reported in an individual affected 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 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 Clinical Services Laboratory,Illumina RCV001099856 SCV001256345 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286509 SCV001473095 uncertain significance none 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.

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