Submissions for variant NM_000318.3(PEX2):c.282A>T (p.Arg94Ser)

gnomAD frequency: 0.00046  dbSNP: rs140963177

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732005	SCV000859880	uncertain significance	not provided	2018-02-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001163870	SCV001325954	uncertain significance	Peroxisome biogenesis disorder 5A (Zellweger)	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	RCV001163870	SCV001420330	uncertain significance	Peroxisome biogenesis disorder 5A (Zellweger)	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 94 of the PEX2 protein (p.Arg94Ser). This variant is present in population databases (rs140963177, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PEX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 596242). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PEX2 protein function. 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.
Elsea Laboratory, Baylor College of Medicine	RCV001250053	SCV001424205	uncertain significance	Peroxisome biogenesis disorder 5A (Zellweger); Peroxisome biogenesis disorder 5B	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002535252	SCV003703855	uncertain significance	Inborn genetic diseases	2022-05-02	criteria provided, single submitter	clinical testing	The c.282A>T (p.R94S) alteration is located in exon 4 (coding exon 1) of the PEX2 gene. This alteration results from a A to T substitution at nucleotide position 282, causing the arginine (R) at amino acid position 94 to be replaced by a serine (S). The p.R94S alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003918211	SCV004737374	likely benign	PEX2-related condition	2024-02-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001825468	SCV002083374	uncertain significance	Zellweger spectrum disorders	2019-10-28	no assertion criteria provided	clinical testing