NM_000466.3(PEX1):c.2227-1G>C AND Zellweger spectrum disorders

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 14, 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:: RCV003594957.2

Allele description [Variation Report for NM_000466.3(PEX1):c.2227-1G>C]

NM_000466.3(PEX1):c.2227-1G>C

Gene:

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.2227-1G>C

HGVS:

NC_000007.14:g.92502080C>G
NG_008341.2:g.31452G>C
NM_000466.3:c.2227-1G>CMANE SELECT
NM_001282677.2:c.2056-1G>C
NM_001282678.2:c.1603-1G>C
NC_000007.13:g.92131394C>G

Molecular consequence:

NM_000466.3:c.2227-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282677.2:c.2056-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282678.2:c.1603-1G>C - 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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daa90h07.y1 Wellcome CRC pRN3 St13 17 egg animal cap Xenopus laevis cDNA clone I...
daa90h07.y1 Wellcome CRC pRN3 St13 17 egg animal cap Xenopus laevis cDNA clone IMAGE:4084837 5' similar to SW:FKH1_XENLA P33206 XFKH1 PROTEIN, mRNA sequence
gi|14287527|gnl|dbEST|8672135|gb|BG 7.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004365133	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 21031596, 26387595, 31831025, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004365133

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (5)
[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

Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder.

Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR.

Hum Mutat. 2011 Jan;32(1):59-69. doi: 10.1002/humu.21388.

PubMed [citation]

PMID:: 21031596

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004365133.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 13 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PEX1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	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: Sep 29, 2024

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