ClinVar Miner

Submissions for variant NM_000286.3(PEX12):c.126+1G>T (rs144259891)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410810 SCV000487539 pathogenic Infantile Refsum's disease 2016-08-16 criteria provided, single submitter clinical testing
Counsyl RCV000412365 SCV000487540 pathogenic Peroxisome biogenesis disorder 3A 2016-08-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000730395 SCV000858128 pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589854 SCV000696481 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 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.
Invitae RCV000412365 SCV000940796 pathogenic Peroxisome biogenesis disorder 3A 2019-01-16 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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs144259891, ExAC 0.006%). This variant has been observed in several individuals affected 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, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.

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