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

gnomAD frequency: 0.00011  dbSNP: rs148591292

Total submissions: 19

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 (ga)	RCV000579182	SCV000331543	pathogenic	not provided	2015-03-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388756	SCV000460549	pathogenic	PEX7-related disorder	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	2024-05-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on splicing with skipping of exon 9, leading to premature termination of the protein (PMID: 9090383); Also known as IVS9+1G>C; This variant is associated with the following publications: (PMID: 12325024, 25525159, 11781871, 23572185, 26408048, 31589614, 31980526, 31964843, 9090383)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000309699	SCV000819782	pathogenic	Peroxisome biogenesis disorder 9B	2024-07-05	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 disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs148591292, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 9090383, 11781871, 12325024, 23572185, 26408048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7785). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a new termination codon (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 Genetics, 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.
Fulgent Genetics, Fulgent Genetics	RCV005003344	SCV002809824	pathogenic	Rhizomelic chondrodysplasia punctata type 1; Peroxisome biogenesis disorder 9B	2024-03-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000309699	SCV004201628	pathogenic	Peroxisome biogenesis disorder 9B	2024-03-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000579182	SCV004229836	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with rhizomelic chondrodysplasia punctata (RCDP), this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing. Studies show this variant will result in premature termination of the protein (PMID: 9090383, 12325024).
OMIM	RCV000008227	SCV000028434	pathogenic	Rhizomelic chondrodysplasia punctata type 1	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000008227	SCV000055663	not provided	Rhizomelic chondrodysplasia punctata type 1		no assertion provided	literature only
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	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