Submissions for variant NM_000466.3(PEX1):c.3208-1G>A

gnomAD frequency: 0.00001  dbSNP: rs1057517518

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000599082	SCV000707639	pathogenic	not provided	2017-04-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000599082	SCV000710583	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Reported in the heterozygous state in a patient in published literature with cone-rod dystrophy, however variants identified in other genes were thought to explain the phenotype (PMID: 27353947); This variant is associated with the following publications: (PMID: 27353947)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376544	SCV001227260	likely pathogenic	Zellweger spectrum disorders	2021-05-28	criteria provided, single submitter	clinical testing	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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). 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. This variant has not been reported in the literature in individuals with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 371765). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 of the PEX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
PreventionGenetics, part of Exact Sciences	RCV003409567	SCV004107248	likely pathogenic	PEX1-related disorder	2023-03-10	criteria provided, single submitter	clinical testing	The PEX1 c.3208-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92120817-C-T). Variants that disrupt the consensus splice acceptor site in PEX1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003475988	SCV004203280	pathogenic	Heimler syndrome 1	2024-03-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000411432	SCV000487694	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2019-07-12	no assertion criteria provided	clinical testing
Counsyl	RCV000409017	SCV000487695	likely pathogenic	Peroxisome biogenesis disorder 1B	2019-07-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001376544	SCV002076817	likely pathogenic	Zellweger spectrum disorders	2017-11-09	no assertion criteria provided	clinical testing