ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.903+1G>C (rs148591292)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000008227 SCV000194625 pathogenic Rhizomelic chondrodysplasia punctata type 1 2014-05-22 criteria provided, single submitter clinical testing
Eurofins NTD, LLC RCV000579182 SCV000331543 pathogenic not provided 2015-03-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000388756 SCV000460549 pathogenic PEX7-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The PEX7 c.903+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.903+1G>C variant has been reported in four studies in which it is found in at least 23 patients with rhizomelic chondrodysplasia punctate, including two in a homozygous state, 15 in a compound heterozygous state, and six individuals of unknown zygosity (Braverman et al. 2002; Motley et al. 2002; Huffnagel et al. 2013; Duker et al. 2016). The variant was absent from at least 100 control chromosomes and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Northern blot analysis on PEX7 mRNA from an individual who was homozygous for the c.903+1G>C variant revealed a band that corresponded to a shorter transcript than in controls, which was the result of exon skipping (Braverman et al. 2002). Based on the collective evidence and the potential impact of splice donor variants, the c.903+1G>C variant is classified as pathogenic for PEX7-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000579182 SCV000680695 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The c.903+1 G>C splice site variant in the PEX7 gene has been previously reported in association with rhizomelic chondrodysplasia punctata type 1 (Motley et al., 2002; Huffnagel et al., 2013; Braverman et al., 2002). Functional studies have shown this pathogenic variant destroys the canonical splice donor site in intron 9, and results in abnormal splicing (Purdue et al., 1997). The c.903+1 G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.903+1 G>C as a pathogenic variant.
Invitae RCV000309699 SCV000819782 pathogenic Peroxisome biogenesis disorder 9B 2020-10-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the PEX7 gene. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs148591292, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another PEX7 variant in individuals affected with rhizomelic chondrodysplasia punctata (PMID: 9090383, 11781871, 12325024, 23572185, 26408048). This variant is also known as IVS9+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 7785). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with skipping of exon 9, which introduces a frameshift (PMID: 9090383). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008227 SCV000919981 pathogenic Rhizomelic chondrodysplasia punctata type 1 2018-03-29 criteria provided, single submitter clinical testing Variant summary: PEX7 c.903+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. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Braverman 2002). The variant allele was found at a frequency of 6.9e-05 in 276934 control chromosomes. c.903+1G>C has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (e.g. Motley 2002, Huffnagel 2013, Braverman 2002). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000008227 SCV001163005 pathogenic Rhizomelic chondrodysplasia punctata type 1 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000008227 SCV001193825 pathogenic Rhizomelic chondrodysplasia punctata type 1 2019-12-19 criteria provided, single submitter clinical testing NM_000288.3(PEX7):c.903+1G>C(aka IVS9+1G>C) is classified as pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 9090383 and 12325024. Classification of NM_000288.3(PEX7):c.903+1G>C(aka IVS9+1G>C) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000309699 SCV001366292 pathogenic Peroxisome biogenesis disorder 9B 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2,PP3.
OMIM RCV000008227 SCV000028434 pathogenic Rhizomelic chondrodysplasia punctata type 1 2002-10-01 no assertion criteria provided literature only
GeneReviews RCV000008227 SCV000055663 pathologic Rhizomelic chondrodysplasia punctata type 1 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV001027954 SCV001190696 pathogenic Rhizomelic chondrodysplasia punctata 2019-05-20 no assertion criteria provided clinical testing
Natera, Inc. RCV000008227 SCV001459670 pathogenic Rhizomelic chondrodysplasia punctata type 1 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000579182 SCV001740799 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000579182 SCV001952159 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000579182 SCV001979055 pathogenic not provided no assertion criteria provided clinical testing

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