Submissions for variant NM_000287.4(PEX6):c.659G>T (p.Gly220Val)

dbSNP: rs267608203

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672728	SCV000797863	uncertain significance	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B	2018-02-13	criteria provided, single submitter	clinical testing
Invitae	RCV002534243	SCV003439383	uncertain significance	Peroxisome biogenesis disorder	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 220 of the PEX6 protein (p.Gly220Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PEX6-related conditions (PMID: 19877282, 26275793, 31884617). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 545099). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Baylor Genetics	RCV003472050	SCV004201596	likely pathogenic	Heimler syndrome 2	2022-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488777	SCV004241837	uncertain significance	not specified	2023-12-05	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.659G>T (p.Gly220Val) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). c.659G>T has been reported in the literature in individuals affected with features of Zellweger Syndrome (Ebberink_2010, Mechaussier_2019). These data indicate that the variant may 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: 19877282, 26275793, 31884617). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000656322	SCV000778297	pathogenic	not provided	2018-01-03	no assertion criteria provided	clinical testing