ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.188+1G>C (rs267608254)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169353 SCV000220723 pathogenic Rhizomelic chondrodysplasia punctata type 1 2014-09-24 criteria provided, single submitter literature only
Baylor Genetics RCV000169353 SCV001162995 pathogenic Rhizomelic chondrodysplasia punctata type 1 criteria provided, single submitter clinical testing
Invitae RCV001068245 SCV001233344 likely pathogenic Peroxisome biogenesis disorder 9B 2020-10-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the PEX7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with rhizomelic chondrodysplasia punctata (PMID: 12325024). This variant is also known as IVS2+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 188975). 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 PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169353 SCV001442631 pathogenic Rhizomelic chondrodysplasia punctata type 1 2020-10-12 criteria provided, single submitter clinical testing Variant summary: PEX7 c.188+1G>C (also known as IVS2+1G>C) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. At-least one in-silico prediction tool, Transcript-inferred Pathogenicity score (TraP), predicts a possible pathogenic outcome for this variant. The variant allele was found at a frequency of 1.2e-05 in 251450 control chromosomes (gnomAD). c.188+1G>C has been reported in the literature in individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (e.g. Braverman_2002). These data indicate that the variant is likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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