NM_000466.3(PEX1):c.2926+1G>A AND Zellweger spectrum disorders

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 21, 2023
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:: RCV002228604.11

Allele description [Variation Report for NM_000466.3(PEX1):c.2926+1G>A]

NM_000466.3(PEX1):c.2926+1G>A

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.2

Genomic location:

Preferred name:

NM_000466.3(PEX1):c.2926+1G>A

HGVS:

NC_000007.14:g.92494486C>T
NG_008341.2:g.39046G>A
NM_000466.3:c.2926+1G>AMANE SELECT
NM_001282677.2:c.2755+1G>A
NM_001282678.2:c.2302+1G>A
NC_000007.13:g.92123800C>T
NM_000466.2:c.2926+1G>A

Links:

dbSNP: rs267608179

NCBI 1000 Genomes Browser:

rs267608179

Molecular consequence:

NM_000466.3:c.2926+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001282677.2:c.2755+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001282678.2:c.2302+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000963840	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16199547, 26387595, 31831025, 15542397, 19105186, 21031596, 9398847, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000963840

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.

Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, et al.

Am J Hum Genet. 2015 Oct 1;97(4):535-45. doi: 10.1016/j.ajhg.2015.08.011. Epub 2015 Sep 17.

PubMed [citation]

PMID:: 26387595
PMCID:: PMC4596894

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000963840.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change affects a donor splice site in intron 18 of the PEX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs267608179, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Zellweger syndrome spectrum disorders (PMID: 15542397, 19105186, 21031596). ClinVar contains an entry for this variant (Variation ID: 188729). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects PEX1 function (PMID: 9398847). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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: Nov 3, 2024

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