Submissions for variant NM_000286.3(PEX12):c.987_988del (p.Phe330fs)

dbSNP: rs764657253

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239384	SCV001412257	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe330Serfs*23) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs764657253, 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: 557980). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Gln337*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226365	SCV003922616	likely pathogenic	Peroxisome biogenesis disorder	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: PEX12 c.987_988delGT (p.Phe330SerfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Variants downstream of this position have been cited as pathogenic and disease-associated in ClinVar and HGMD and have been reported in affected individuals (PMIDs: 15542397, 33123925). The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.987_988delGT in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001239384	SCV004201439	likely pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2024-01-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000674189	SCV000799481	uncertain significance	Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger)	2018-04-19	flagged submission	clinical testing