VCV000009143.8 - ClinVar

NM_001351132.2(PEX5):c.1578T>G (p.Asn526Lys)

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.

(7)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001351132.2(PEX5):c.1578T>G (p.Asn526Lys)

Variation ID: 9143 Accession: VCV000009143.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 7209700 (GRCh38) [ NCBI UCSC ] 12: 7362296 (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	Mar 8, 2017	Feb 4, 2024	May 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001351132.2:c.1578T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001338061.1:p.Asn526Lys	missense
NM_000319.5:c.1554T>G	NP_000310.2:p.Asn518Lys	missense
NM_001131023.2:c.1623T>G	NP_001124495.1:p.Asn541Lys	missense
NM_001131024.2:c.1467T>G	NP_001124496.1:p.Asn489Lys	missense
NM_001131025.2:c.1578T>G	NP_001124497.1:p.Asn526Lys	missense
NM_001131026.2:c.1578T>G	NP_001124498.1:p.Asn526Lys	missense
NM_001300789.3:c.1578T>G	NP_001287718.2:p.Asn526Lys	missense
NM_001351124.3:c.1467T>G	NP_001338053.1:p.Asn489Lys	missense
NM_001351126.2:c.1467T>G	NP_001338055.1:p.Asn489Lys	missense
NM_001351127.2:c.1467T>G	NP_001338056.1:p.Asn489Lys	missense
NM_001351128.2:c.1467T>G	NP_001338057.1:p.Asn489Lys	missense
NM_001351130.3:c.1467T>G	NP_001338059.1:p.Asn489Lys	missense
NM_001351131.2:c.1578T>G	NP_001338060.1:p.Asn526Lys	missense
NM_001351133.2:c.1578T>G	NP_001338062.1:p.Asn526Lys	missense
NM_001351134.2:c.1578T>G	NP_001338063.1:p.Asn526Lys	missense
NM_001351135.3:c.1512T>G	NP_001338064.2:p.Asn504Lys	missense
NM_001351136.2:c.1569T>G	NP_001338065.1:p.Asn523Lys	missense
NM_001351137.3:c.1467T>G	NP_001338066.2:p.Asn489Lys	missense
NM_001351138.2:c.1512T>G	NP_001338067.1:p.Asn504Lys	missense
NM_001351139.2:c.1443T>G	NP_001338068.1:p.Asn481Lys	missense
NM_001351140.2:c.1443T>G	NP_001338069.1:p.Asn481Lys	missense
NM_001374645.1:c.1467T>G	NP_001361574.1:p.Asn489Lys	missense
NM_001374646.1:c.1467T>G	NP_001361575.1:p.Asn489Lys	missense
NM_001374647.2:c.1578T>G	NP_001361576.1:p.Asn526Lys	missense
NM_001374648.2:c.1467T>G	NP_001361577.1:p.Asn489Lys	missense
NM_001374649.2:c.1443T>G	NP_001361578.1:p.Asn481Lys	missense
NC_000012.12:g.7209700T>G
NC_000012.11:g.7362296T>G
NG_008448.1:g.25538T>G

... more HGVS ... less HGVS

Protein change

N489K, N518K, N526K, N541K, N547K, N523K, N481K, N504K

Other names

Canonical SPDI

NC_000012.12:7209699:T:G

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.

Links

ClinGen: CA254664 OMIM: 600414.0001 dbSNP: rs61752138 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.
PEX5		-	-	GRCh38 GRCh38 GRCh37	991	1043

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 2B	Pathogenic (2)	no assertion criteria provided	Jun 26, 2018	RCV000009714.3
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 19, 2021	RCV000427819.6
Peroxisome biogenesis disorder 2A (Zellweger)	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 8, 2023	RCV000723322.4

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.
Pathogenic (May 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peroxisome biogenesis disorder 2A (Zellweger) Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001525319.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Mar 28, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000516541.4 First in ClinVar: Mar 08, 2017 Last updated: Jul 24, 2021	Comment: Published functional studies demonstrate a damaging effect (Dodt et al., 1995; Shimozawa et al., 1999; Carvalho et al., 2007); Not observed in large population cohorts … (more) Published functional studies demonstrate a damaging effect (Dodt et al., 1995; Shimozawa et al., 1999; Carvalho et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31130284, 11101887, 7719337, 10462504, 18712838, 17532062) (less)
Likely pathogenic (Nov 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003811354.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Peroxisome biogenesis disorder 2A (Zellweger) Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV003924308.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Pathogenic (Feb 01, 1995)	no assertion criteria provided Method: literature only	PEROXISOME BIOGENESIS DISORDER 2B Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029932.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 24, 2018	Publications: PubMed (1) PubMed: 7719337 Comment on evidence: In a cell line from a patient with neonatal adrenoleukodystrophy (see PBD2B, 202370), Dodt et al. (1995) identified a specific defect in PTS1-mediated uptake of … (more) In a cell line from a patient with neonatal adrenoleukodystrophy (see PBD2B, 202370), Dodt et al. (1995) identified a specific defect in PTS1-mediated uptake of peroxisomal proteins and examined the PXR1 gene in this patient by RT-PCR amplification of fibroblast RNA followed by SSCP analysis. Sequencing of an abnormally migrating fragment demonstrated a PXR1 allele with a T-to-G transversion at basepair 1467, producing an asn489-to-lys (N489K) substitution. The patient appeared to be homozygous for the mutant allele, but family studies were not performed. The N489K substitution was not found in 130 unrelated control individuals. Transfection of the normal gene into the patient's cells restored normal import of PTS1-containing proteins into peroxisomes, as well as normal peroxisome morphology. In contrast, normal cells transfected with PXR1 carrying the N489K mutation were unable to import PTS1-containing proteins into peroxisomes. (The cells of the patient showed normal import of the PTS2 marker protein, thiolase, into peroxisomal structures.) (less)
Pathogenic (Jun 26, 2018)	no assertion criteria provided Method: clinical testing	Peroxisome biogenesis disorder 2A (Zellweger) Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV000854715.1 First in ClinVar: Dec 09, 2018 Last updated: Dec 09, 2018
Pathogenic (Jun 26, 2018)	no assertion criteria provided Method: clinical testing	Peroxisome biogenesis disorder 2B Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV000854716.1 First in ClinVar: Aug 24, 2018 Last updated: Aug 24, 2018

Comment:

Published functional studies demonstrate a damaging effect (Dodt et al., 1995; Shimozawa et al., 1999; Carvalho et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31130284, 11101887, 7719337, 10462504, 18712838, 17532062)

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
Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders.	Dodt G	Nature genetics	1995	PMID: 7719337

Text-mined citations for rs61752138 ...

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 Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_001351132.2(PEX5):c.1578T>G (p.Asn526Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752138 ...