NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs) AND Peroxisome biogenesis disorder 4A (Zellweger)

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000410284.15

Allele description [Variation Report for NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)]

NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)

Gene:

PEX6:peroxisomal biogenesis factor 6 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)

HGVS:

NC_000006.12:g.42969720_42969727del
NG_008370.1:g.14523_14530del
NM_000287.4:c.1314_1321delMANE SELECT
NM_001316313.2:c.1050_1057del
NP_000278.3:p.Glu439fs
NP_001303242.1:p.Glu351fs
NC_000006.11:g.42937452_42937459del
NC_000006.11:g.42937458_42937465del
NM_000287.3:c.1314_1321del
NM_000287.3:c.1314_1321delGGAGGCCT
NM_000287.4:c.1314_1321delGGAGGCCTMANE SELECT
NR_133009.2:n.1345_1352del

Protein change:

E351fs

Links:

dbSNP: rs267608216

NCBI 1000 Genomes Browser:

rs267608216

Molecular consequence:

NM_000287.4:c.1314_1321del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001316313.2:c.1050_1057del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_133009.2:n.1345_1352del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Peroxisome biogenesis disorder 4A (Zellweger) (PBD4A)
Synonyms:: Zellweger syndrome spectrum (PEX6-related)
Identifiers:: MONDO: MONDO:0013930; MedGen: C3553936; Orphanet: 912; OMIM: 614862

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487547	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Jul 5, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19142205, 19877282 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000916143	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Mar 28, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27302843, 24016303, 19877282, 19142205 Citation Link,
SCV001368694	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001425342	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19142205, 19877282, 22871920, 27302843, 25741868
SCV004045815	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Sep 18, 2023)	paternal	clinical testing	Citation Link,
SCV005051926	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder.

Berendse K, Ebberink MS, Ijlst L, Poll-The BT, Wanders RJ, Waterham HR.

Orphanet J Rare Dis. 2013 Sep 9;8:138. doi: 10.1186/1750-1172-8-138.

PubMed [citation]

PMID:: 24016303
PMCID:: PMC3844471

Rational diagnostic strategy for Zellweger syndrome spectrum patients.

Krause C, Rosewich H, Gärtner J.

Eur J Hum Genet. 2009 Jun;17(6):741-8. doi: 10.1038/ejhg.2008.252. Epub 2009 Jan 14.

PubMed [citation]

PMID:: 19142205
PMCID:: PMC2947092

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000487547.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The PEX6 c.1314_1321delGGAGGCCT (p.Glu439GlyfsTer3) variant has been reported in four studies and identified in at least seven individuals with Zellweger syndrome, including five homozygotes and two compound heterozygotes (Krause et al. 2009; Ebberink et al. 2010; Berendse et al. 2013; Smith et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000260 in the South Asian population of the Genome Aggregation Database. Studies done by Berendse et al. (2013) showed that skin fibroblasts from an affected compound heterozygous individual with a second missense variant showed an increase in the number of peroxisome positive cells after being treated with 20mM of arginine for 21 days. Due to the potential impact of frameshift variants and the evidence from the literature, the p.Glu439GlyfsTer3 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368694.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PS4,PS3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425342.1

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

#	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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045815.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	paternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051926.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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