Submissions for variant NM_000286.3(PEX12):c.362TTC[2] (p.Leu123del)

dbSNP: rs751058068

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000440158	SCV000511636	uncertain significance	not provided	2016-09-08	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Counsyl	RCV000672446	SCV000797552	uncertain significance	Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger)	2018-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000989843	SCV001140434	likely pathogenic	Peroxisome biogenesis disorder type 3B	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000440158	SCV002009276	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV001861489	SCV002152700	uncertain significance	Peroxisome biogenesis disorder 3A (Zellweger)	2022-10-30	criteria provided, single submitter	clinical testing	This variant, c.368_370del, results in the deletion of 1 amino acid(s) of the PEX12 protein (p.Leu123del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751058068, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PEX12-related conditions. ClinVar contains an entry for this variant (Variation ID: 377276). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282136	SCV002572317	uncertain significance	not specified	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: PEX12 c.368_370delTTC (p.Leu123del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251230 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, described as p.Leu123del, has been reported in the literature in the heterozygous state (i.e. without an identified second variant) in at-least one individual, who was affected with mild clinical phenotype of the Zellweger Syndrome spectrum (Soliman_2018). Authors of this study also performed functional studies with patient derived fibroblasts and demonstrated both peroxisomal- and Zellweger-like cytoplasmic catalase localization, decreased cellular peroxisome number, and additional cellular alterations (Soliman_2018). This report does not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.