Submissions for variant NM_000287.4(PEX6):c.2579G>A (p.Arg860Gln)

gnomAD frequency: 0.00002  dbSNP: rs61753231

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265583	SCV001443748	likely pathogenic	PEX6-related disorder	2019-11-19	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change with a c.1802G>A (p.Arg601Gln) variant in a patient with peroxisome biogenesis disorder (Zellweger syndrome) (PMID: 19105186). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0020% (5/251,342) and thus is presumed to be rare. This variant has not been reported in ClinVar, but a different missense variant at the same amino acid residue c.2578C>T (p.Arg860Trp) has been classified as Pathogenic by an external laboratory (Variation ID: 492968). The c.2579G>A (p.Arg860Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2579G>A (p.Arg860Gln) variant is classified as Likely Pathogenic.
Invitae	RCV001309121	SCV001498607	likely pathogenic	Peroxisome biogenesis disorder	2023-09-08	criteria provided, single submitter	clinical testing	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 expected to disrupt PEX6 protein function. ClinVar contains an entry for this variant (Variation ID: 984940). This missense change has been observed in individual(s) with Zellweger syndrome spectrum (PMID: 19105186). This variant is present in population databases (rs61753231, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 860 of the PEX6 protein (p.Arg860Gln). This variant disrupts the p.Arg860 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003473843	SCV004201567	likely pathogenic	Heimler syndrome 2	2023-05-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830065	SCV002077275	uncertain significance	Zellweger spectrum disorders	2021-03-31	no assertion criteria provided	clinical testing