VCV000556176.12 - ClinVar

NM_000466.3(PEX1):c.2846G>A (p.Arg949Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000466.3(PEX1):c.2846G>A (p.Arg949Gln)

Variation ID: 556176 Accession: VCV000556176.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.2 7: 92494567 (GRCh38) [ NCBI UCSC ] 7: 92123881 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Nov 10, 2024	Oct 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000466.3:c.2846G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000457.1:p.Arg949Gln	missense
NM_001282677.2:c.2675G>A	NP_001269606.1:p.Arg892Gln	missense
NM_001282678.2:c.2222G>A	NP_001269607.1:p.Arg741Gln	missense
NC_000007.14:g.92494567C>T
NC_000007.13:g.92123881C>T
NG_008341.2:g.38965G>A

... more HGVS ... less HGVS

Protein change

R949Q, R741Q, R892Q

Other names

Canonical SPDI

NC_000007.14:92494566:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Links

dbSNP: rs61750425 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GATAD1		-	-	GRCh38 GRCh37	130	751
PEX1		-	-	GRCh38 GRCh37	1288	1869

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Peroxisome biogenesis disorder 1A (Zellweger)	Uncertain significance (1)	criteria provided, single submitter	Jan 16, 2018	RCV000672142.1
Zellweger spectrum disorders	Likely pathogenic (1)	criteria provided, single submitter	Oct 30, 2023	RCV001242973.6
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 30, 2024	RCV001662740.4
Heimler syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Mar 28, 2024	RCV003472144.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 16, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Peroxisome biogenesis disorder 1A (Zellweger) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000797212.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 21031596‚ 11389485
Likely pathogenic (Oct 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Zellweger spectrum disorders Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001416099.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 11389485‚ 21031596‚ 31964843‚ 21844578‚ 27469511 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 949 of the PEX1 protein (p.Arg949Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 949 of the PEX1 protein (p.Arg949Gln). This variant is present in population databases (rs61750425, gnomAD 0.007%). This missense change has been observed in individuals with a Zellweger syndrome spectrum disorder (PMID: 11389485, 21031596, 31964843; Invitae). ClinVar contains an entry for this variant (Variation ID: 556176). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg949 amino acid residue in PEX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21031596, 21844578, 27469511). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
Likely pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Heimler syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004203354.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Oct 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001873474.3 First in ClinVar: Sep 19, 2021 Last updated: Nov 10, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16086329, 15542397, 31374812, 34426522, 11389485, 31964843, 35586607, 21031596) (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 949 of the PEX1 protein (p.Arg949Gln). This variant is present in population databases (rs61750425, gnomAD 0.007%). This missense change has been observed in individuals with a Zellweger syndrome spectrum disorder (PMID: 11389485, 21031596, 31964843; Invitae). ClinVar contains an entry for this variant (Variation ID: 556176). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg949 amino acid residue in PEX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21031596, 21844578, 27469511). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16086329, 15542397, 31374812, 34426522, 11389485, 31964843, 35586607, 21031596)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.	Hanany M	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31964843
Cholic acid therapy in Zellweger spectrum disorders.	Berendse K	Journal of inherited metabolic disease	2016	PMID: 27469511
Two novel PEX1 mutations in a patient with Zellweger syndrome: the first Korean case confirmed by biochemical, and molecular evidence.	Cho SY	Annals of clinical and laboratory science	2011	PMID: 21844578
Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder.	Ebberink MS	Human mutation	2011	PMID: 21031596
Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels.	Walter C	American journal of human genetics	2001	PMID: 11389485

Text-mined citations for rs61750425 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000466.3(PEX1):c.2846G>A (p.Arg949Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61750425 ...