VCV000495796.27 - ClinVar

NM_000287.4(PEX6):c.1947del (p.Ile650fs)

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.

(10)

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_000287.4(PEX6):c.1947del (p.Ile650fs)

Variation ID: 495796 Accession: VCV000495796.27

Type and length

Deletion, 1 bp

Location

Cytogenetic: 6p21.1 6: 42966796 (GRCh38) [ NCBI UCSC ] 6: 42934534 (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 17, 2018	Dec 22, 2024	Mar 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000287.4:c.1947del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000278.3:p.Ile650fs	frameshift
NM_000287.3:c.1947del
NM_001316313.2:c.1683del	NP_001303242.1:p.Ile562fs	frameshift
NR_133009.2:n.1978del		non-coding transcript variant
NC_000006.12:g.42966797del
NC_000006.11:g.42934535del
NG_008370.1:g.17448del

... more HGVS ... less HGVS

Protein change

I562fs, I650fs

Other names

Canonical SPDI

NC_000006.12:42966795:CC:C

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: CA3811174 dbSNP: rs267608227 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.
PEX6		-	-	GRCh38 GRCh37	1759	1779

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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV000586808.8
Peroxisome biogenesis disorder 4B	Pathogenic (2)	criteria provided, single submitter	Jul 17, 2023	RCV000665650.2
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 1, 2022	RCV000734107.18
Peroxisome biogenesis disorder 4A (Zellweger)	Pathogenic (1)	criteria provided, single submitter	Sep 18, 2023	RCV003336085.4
Zellweger spectrum disorders	Pathogenic (1)	no assertion criteria provided	Aug 26, 2020	RCV001834835.1
Heimler syndrome 2	Pathogenic (1)	criteria provided, single submitter	Mar 18, 2024	RCV003471938.2

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.
Pathogenic (Sep 09, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Peroxisome biogenesis disorder Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696485.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 19142205‚ 21031596 Comment: Variant summary: The PEX6 c.1947delG (p.Ile650Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX6 protein due to nonsense … (more) Variant summary: The PEX6 c.1947delG (p.Ile650Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121404 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365). The variant has been reported in affected individuals in the literature in the homozygous and heterozygous state. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Jun 29, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000862220.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX6 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Sep 18, 2023)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Peroxisome biogenesis disorder 4A (Zellweger) (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045814.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Large fontanelles (present) , Severe muscular hypotonia (present) , Feeding difficulties (present) , Respiratory insufficiency (present)
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003824876.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Peroxisome biogenesis disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000963976.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10408779‚ 21031596‚ 31831025‚ 19142205‚ 19877282 Comment: This sequence change creates a premature translational stop signal (p.Ile650Serfs10) in the PEX6 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ile650Serfs10) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (rs267608227, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Zellweger syndrome (PMID: 19142205, 19877282). ClinVar contains an entry for this variant (Variation ID: 495796). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Heimler syndrome 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201532.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peroxisome biogenesis disorder 4B (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005400229.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 19877282‚ 29220678 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with peroxisome biogenesis disorder 4B (MIM#614863), Heimler syndrome 2 (MIM#616617) and peroxisome biogenesis disorder 4A (Zellweger; MIM#614862). (I) 0108 - This gene is associated with both recessive and dominant disease. The recurrent variant p.(Arg860Trp) is associated with autosomal dominant peroxisome biogenesis disorder 4B (PMID: 29220678). In addition, Heimler syndrome 2 is milder due to one allele encoding for a protein with residual function (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in both homozygous and heterozygous individuals with Zellweger syndrome (PMID: 19877282). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (Aug 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004161624.11 First in ClinVar: Nov 20, 2023 Last updated: Dec 22, 2024	Comment: PEX6: PVS1, PS4:Supporting Number of individuals with the variant: 1
Pathogenic (Feb 21, 2017)	no assertion criteria provided Method: clinical testing	Peroxisome biogenesis disorder 4B Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000789804.2 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 19877282‚ 19142205
Pathogenic (Aug 26, 2020)	no assertion criteria provided Method: clinical testing	Zellweger syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002077290.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

Variant summary: The PEX6 c.1947delG (p.Ile650Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121404 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365). The variant has been reported in affected individuals in the literature in the homozygous and heterozygous state. Taken together, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ile650Serfs*10) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (rs267608227, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Zellweger syndrome (PMID: 19142205, 19877282). ClinVar contains an entry for this variant (Variation ID: 495796). For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with peroxisome biogenesis disorder 4B (MIM#614863), Heimler syndrome 2 (MIM#616617) and peroxisome biogenesis disorder 4A (Zellweger; MIM#614862). (I) 0108 - This gene is associated with both recessive and dominant disease. The recurrent variant p.(Arg860Trp) is associated with autosomal dominant peroxisome biogenesis disorder 4B (PMID: 29220678). In addition, Heimler syndrome 2 is milder due to one allele encoding for a protein with residual function (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in both homozygous and heterozygous individuals with Zellweger syndrome (PMID: 19877282). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Expanding the clinical and genetic spectrum of Heimler syndrome.	Gao FJ	Orphanet journal of rare diseases	2019	PMID: 31831025
Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.	Falkenberg KD	American journal of human genetics	2017	PMID: 29220678
Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder.	Ebberink MS	Human mutation	2011	PMID: 21031596
Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.	Ebberink MS	Human mutation	2010	PMID: 19877282
Rational diagnostic strategy for Zellweger syndrome spectrum patients.	Krause C	European journal of human genetics : EJHG	2009	PMID: 19142205
Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.	Zhang Z	Human mutation	1999	PMID: 10408779
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX6	-	-	-	-

Text-mined citations for rs267608227 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000287.4(PEX6):c.1947del (p.Ile650fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608227 ...