ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.345T>G (p.Tyr115Ter) (rs121909154)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411170 SCV000486131 likely pathogenic Rhizomelic chondrodysplasia punctata type 1 2016-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411170 SCV000919982 pathogenic Rhizomelic chondrodysplasia punctata type 1 2018-05-24 criteria provided, single submitter clinical testing Variant summary: PEX7 c.345T>G (p.Tyr115X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study confirmed that this variant is triggering nonsense-mediated decay with lack of a full length transcript (Braverman_2002). The variant allele was found at a frequency of 4.1e-05 in 246196 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PEX7 causing Rhizomelic Chondrodysplasia Punctata Type 1 (4.1e-05 vs 1.90e-03), allowing no conclusion about variant significance. The variant, c.345T>G, has been reported in the literature in individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (Motley_PEX7_AMJHumGenet_2002) and the subphenotype adult Refsum disease (ARD) when found in compound heterozygosity with IVS3-10A>G (Braverman_2002). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classifies the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000008228 SCV001388016 pathogenic Peroxisome biogenesis disorder 9B 2019-05-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr115*) in the PEX7 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121909154, ExAC 0.01%). This variant has been observed in an individual with rhizomelic chondrodysplasia punctata type 1 (PMID: 11781871). ClinVar contains an entry for this variant (Variation ID: 7786). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008228 SCV000028435 pathogenic Peroxisome biogenesis disorder 9B 2007-02-27 no assertion criteria provided literature only

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