NM_000466.3(PEX1):c.3637-3_3637-1del AND Zellweger spectrum disorders

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 2, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001379471.6

Allele description [Variation Report for NM_000466.3(PEX1):c.3637-3_3637-1del]

NM_000466.3(PEX1):c.3637-3_3637-1del

Genes:

GATAD1:GATA zinc finger domain containing 1 [Gene - OMIM - HGNC]
PEX1:peroxisomal biogenesis factor 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7q21.2

Genomic location:

Preferred name:

NM_000466.3(PEX1):c.3637-3_3637-1del

HGVS:

NC_000007.14:g.92489424_92489426del
NG_008341.2:g.44106_44108del
NM_000466.3:c.3637-3_3637-1delMANE SELECT
NM_001282677.2:c.3466-3_3466-1del
NM_001282678.2:c.3013-3_3013-1del
NC_000007.13:g.92118738_92118740del

Links:

dbSNP: rs2116039871

NCBI 1000 Genomes Browser:

rs2116039871

Molecular consequence:

NM_000466.3:c.3637-3_3637-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282677.2:c.3466-3_3466-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282678.2:c.3013-3_3013-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Zellweger spectrum disorders (ZS)
Synonyms:: Zellweger syndrome; Zellweger Spectrum Disorder; Zellweger Spectrum
Identifiers:: MONDO: MONDO:0019609; MedGen: C0043459; Orphanet: 912

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577274	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 2, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16199547, 9398847, 16086329, 16141001, 21031596, 26387595, 31831025, 17576681, 9536098, 28492532
SCV002076801	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jun 4, 2018)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577274

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 2, 2020)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002076801

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Jun 4, 2018)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders.

Reuber BE, Germain-Lee E, Collins CS, Morrell JC, Ameritunga R, Moser HW, Valle D, Gould SJ.

Nat Genet. 1997 Dec;17(4):445-8.

PubMed [citation]

PMID:: 9398847

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV001577274.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change affects an acceptor splice site in intron 22 of the PEX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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, 26387595, 31831025). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant is not present in population databases (ExAC no frequency).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002076801.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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