Submissions for variant NM_002617.4(PEX10):c.967C>T (p.Arg323Trp)

gnomAD frequency: 0.00014  dbSNP: rs148903253

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000598306	SCV000706823	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245731	SCV001419034	uncertain significance	Peroxisome biogenesis disorder, complementation group 7	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the PEX10 protein (p.Arg343Trp). This variant is present in population databases (rs148903253, gnomAD 0.01%). 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: 500751). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000598306	SCV001713768	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002531072	SCV003680456	uncertain significance	Inborn genetic diseases	2021-10-06	criteria provided, single submitter	clinical testing	The c.1027C>T (p.R343W) alteration is located in exon 6 (coding exon 6) of the PEX10 gene. This alteration results from a C to T substitution at nucleotide position 1027, causing the arginine (R) at amino acid position 343 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000598306	SCV005334626	uncertain significance	not provided	2023-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783820	SCV005397673	uncertain significance	Peroxisome biogenesis disorder 6B	2024-02-21	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at position 967 of the coding sequence of the PEX10 gene that results in an arginine to tryptophan amino acid change at residue 323 of the peroxisomal biogenesis factor 10 protein. The 323 residue falls in the RING finger domain (UniProt) which plays a role in the ubiquitin ligase activity of the peroxisomal biogenesis factor 10 protein (PMID: 18644345). This is a previously reported variant (ClinVar 500751) that has not been observed in individuals affected by a PEX10-related disorder in the published literature, to our knowledge. This variant is present in 37 of 380896 alleles (0.0097%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Arg323 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PP3
Natera, Inc.	RCV001829668	SCV002094099	uncertain significance	Zellweger spectrum disorders	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751617	SCV005351618	uncertain significance	PEX10-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The PEX10 c.1027C>T variant is predicted to result in the amino acid substitution p.Arg343Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.