Submissions for variant NM_000286.3(PEX12):c.737C>A (p.Ser246Tyr)

gnomAD frequency: 0.00010  dbSNP: rs200413804

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595486	SCV000709522	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765347	SCV000896612	uncertain significance	Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger)	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781712	SCV000919975	uncertain significance	not specified	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: PEX12 c.737C>A (p.Ser246Tyr) results in a non-conservative amino acid change located in the N-terminal domain (IPR006845) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 244714 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PEX12 causing Zellweger Syndrome (0.0002 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.737C>A in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532678	SCV003261628	uncertain significance	Peroxisome biogenesis disorder 3A (Zellweger)	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 246 of the PEX12 protein (p.Ser246Tyr). This variant is present in population databases (rs200413804, gnomAD 0.03%). 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: 502684). 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 not expected to disrupt PEX12 protein function. 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.
Revvity Omics, Revvity	RCV000595486	SCV004235753	uncertain significance	not provided	2023-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004024866	SCV005002201	uncertain significance	Inborn genetic diseases	2024-06-13	criteria provided, single submitter	clinical testing	The c.737C>A (p.S246Y) alteration is located in exon 3 (coding exon 3) of the PEX12 gene. This alteration results from a C to A substitution at nucleotide position 737, causing the serine (S) at amino acid position 246 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV000595486	SCV005192817	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004740362	SCV005366693	uncertain significance	PEX12-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The PEX12 c.737C>A variant is predicted to result in the amino acid substitution p.Ser246Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.