Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589854 | SCV000696481 | pathogenic | Peroxisome biogenesis disorder | 2017-03-23 | criteria provided, single submitter | clinical testing | Variant summary: The PEX12 c.126+1G>T variant involves the alteration of a conserved intronic nucleotide 1 base pair upstream of the exon-intron junction. Mutation Taster predicts a damaging outcome for this variant and 5/5 splice prediction tools predict a significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExACat a frequency of 0.0000329 (4/121406 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX12 variant (0.0015811). Multiple publications have detected and analyzed the variant in patient cohorts. Chang_AJHG_1998 detected the variant in two patients (PBD006 [severely affected] and PBD099 [mildly affected]), both of which were compound heterozygotes, each carrying a different second mutation allele (PBD006 - p.R180ter; PBD099 - c.26_27delCA causing a frameshift). Functional analyses showed a significant reduction in PBD006 mRNA levels (14% of WT levels) and a lesser reduction in PBD099 (70% of WT levels). Additional molecular studies showed that the c.26_27delCA mutation is a partially functional allele, accounting for the differences observed in phenotype severity and mRNA levels, and supporting a pathogenic role for the variant of interest. Another publication, Ebberink_HM_2011, performed high-throughput complementation assays in 613 patient skin fibroblast cell lines and detected the variant of interest in 8 patients (3 homozygous and 5 heterozygous). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Eurofins Ntd Llc |
RCV000730395 | SCV000858128 | pathogenic | not provided | 2017-11-27 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000412365 | SCV000940796 | pathogenic | Peroxisome biogenesis disorder 3A (Zellweger) | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 1 of the PEX12 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs144259891, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with PEX12-related conditions (PMID: 9792857, 21031596). ClinVar contains an entry for this variant (Variation ID: 371718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000730395 | SCV002050445 | likely pathogenic | not provided | 2023-08-29 | criteria provided, single submitter | clinical testing | Observed with a second PEX12 variant on the opposite allele (in trans) in individuals with Zellweger spectrum disorders in published literature (Chang and Gould, 1998; Demaret et al., 2018).; Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15542397, 9632816, 9090384, 16199547, 33123925, 21031596, 29453832, 22871920, 31980526, 9792857) |
Myriad Genetics, |
RCV000412365 | SCV002060355 | pathogenic | Peroxisome biogenesis disorder 3A (Zellweger) | 2021-10-20 | criteria provided, single submitter | clinical testing | NM_000286.2(PEX12):c.126+1G>T is a canonical splice variant classified as pathogenic in the context of peroxisome biogenesis disorder type 3. c.126+1G>T has been observed in cases with relevant disease (PMID: 9792857, 21031596). Functional assessments of this variant are available in the literature (PMID: 9792857). c.126+1G>T has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000286.2(PEX12):c.126+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Fulgent Genetics, |
RCV002505997 | SCV002811126 | pathogenic | Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger) | 2021-12-09 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000412365 | SCV004201437 | pathogenic | Peroxisome biogenesis disorder 3A (Zellweger) | 2024-03-29 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000730395 | SCV001930177 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000730395 | SCV001972866 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |