Submissions for variant NM_000287.4(PEX6):c.2626C>T (p.Arg876Trp)

gnomAD frequency: 0.00001  dbSNP: rs267608246

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666171	SCV000790418	uncertain significance	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B	2017-03-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198918	SCV001369913	uncertain significance	Peroxisome biogenesis disorder 4A (Zellweger)	2020-03-19	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242506	SCV001415598	uncertain significance	Peroxisome biogenesis disorder	2022-07-12	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 876 of the PEX6 protein (p.Arg876Trp). This variant is present in population databases (rs267608246, gnomAD 0.0009%). This missense change has been observed in individual(s) with an autosomal recessive Zellweger syndrome spectrum disorder (PMID: 19877282). ClinVar contains an entry for this variant (Variation ID: 551183). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV002477483	SCV002788868	uncertain significance	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2022-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001242506	SCV003928915	likely pathogenic	Peroxisome biogenesis disorder	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.2626C>T (p.Arg876Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes.c.2626C>T has been reported in the literature in homozygous individuals and compound heterozygotes, who carried a null allele in trans, and all were affected with a milder form of Zellweger Syndrome, including symptoms of retinal dystrophy and hearing loss (Ebberink_2010, Witters_2016, Perea-Romero_2021, Biswas_2021), suggesting that the variant might cause only a partial loss of PEX6 function. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34662339, 19877282, 34448047, 27007981). ClinVar contains an entry for this variant (Variation ID: 551183). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003472077	SCV004201604	uncertain significance	Heimler syndrome 2	2022-07-28	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002477483	SCV005417918	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_Strong+PP4+PP3
Natera, Inc.	RCV001835075	SCV002077273	uncertain significance	Zellweger spectrum disorders	2020-03-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547836	SCV004727209	uncertain significance	PEX6-related disorder	2024-01-05	no assertion criteria provided	clinical testing	The PEX6 c.2626C>T variant is predicted to result in the amino acid substitution p.Arg876Trp. This variant was reported in the compound heterozygous state in an individual with suspected Zellweger syndrome (Witters et al. 2016. PubMed ID: 27007981; Ebberink et al. 2010. PubMed ID: 19877282). This variant was also reported, along with a protein-truncating variant in the same gene, in an individual who presented with retinitis pigmentosa and hearing loss (Perea-Romero et al. 2021. PubMed ID: 34448047). Lastly, this variant was described in the homozygous state in an individual with retinal dystrophy (Biswas et al. 2021. PubMed ID: 34662339). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that c.2626C>T (p.Arg876Trp) may be pathogenic, the clinical significance of this variant is currently classified as uncertain at this time due to the absence of conclusive functional and genetic evidence.