Submissions for variant NM_002617.4(PEX10):c.418G>C (p.Gly140Arg)

gnomAD frequency: 0.00045  dbSNP: rs76530653

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000309150	SCV000355612	uncertain significance	Peroxisome biogenesis disorder 6A (Zellweger)	2018-01-12	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.
Eurofins Ntd Llc (ga)	RCV000676044	SCV000705535	uncertain significance	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000676044	SCV000801778	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037362	SCV001200772	uncertain significance	Peroxisome biogenesis disorder, complementation group 7	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 140 of the PEX10 protein (p.Gly140Arg). This variant is present in population databases (rs76530653, gnomAD 0.2%), 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 PEX10-related conditions. ClinVar contains an entry for this variant (Variation ID: 296280). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics	RCV002480074	SCV002793936	uncertain significance	Peroxisome biogenesis disorder 6A (Zellweger); Peroxisome biogenesis disorder 6B	2021-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002520466	SCV003671081	likely benign	Inborn genetic diseases	2021-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Breakthrough Genomics, Breakthrough Genomics	RCV000676044	SCV005186759	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001272167	SCV001453862	uncertain significance	Zellweger spectrum disorders	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957547	SCV004772485	likely benign	PEX10-related disorder	2022-03-16	no assertion criteria provided	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).