NM_000466.3(PEX1):c.2993G>A (p.Arg998Gln) AND Zellweger spectrum disorders

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2022
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:: RCV001231027.10

Allele description [Variation Report for NM_000466.3(PEX1):c.2993G>A (p.Arg998Gln)]

NM_000466.3(PEX1):c.2993G>A (p.Arg998Gln)

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.2993G>A (p.Arg998Gln)

HGVS:

NC_000007.14:g.92494330C>T
NG_008341.2:g.39202G>A
NM_000466.3:c.2993G>AMANE SELECT
NM_001282677.2:c.2822G>A
NM_001282678.2:c.2369G>A
NP_000457.1:p.Arg998Gln
NP_001269606.1:p.Arg941Gln
NP_001269607.1:p.Arg790Gln
NC_000007.13:g.92123644C>T
NG_008341.1:g.39202G>A
NM_000466.2:c.2993G>A

Protein change:

R790Q

Links:

dbSNP: rs61750429

NCBI 1000 Genomes Browser:

rs61750429

Molecular consequence:

NM_000466.3:c.2993G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282677.2:c.2822G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282678.2:c.2369G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001403530	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16088892, 28492532
SCV002076828	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jun 19, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001403530

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002076828

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jun 19, 2020)

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

Novel PEX1 coding mutations and 5' UTR regulatory polymorphisms.

Maxwell MA, Leane PB, Paton BC, Crane DI.

Hum Mutat. 2005 Sep;26(3):279.

PubMed [citation]

PMID:: 16088892

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001403530.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX1 protein function. ClinVar contains an entry for this variant (Variation ID: 957949). This missense change has been observed in individual(s) with Zellweger syndrome (PMID: 16088892). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 998 of the PEX1 protein (p.Arg998Gln).

#	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., SCV002076828.1

#	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: Sep 29, 2024

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