VCV000197887.25 - ClinVar

NM_002617.4(PEX10):c.820A>G (p.Thr274Ala)

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.

(11)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002617.4(PEX10):c.820A>G (p.Thr274Ala)

Variation ID: 197887 Accession: VCV000197887.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.32 1: 2406576 (GRCh38) [ NCBI UCSC ] 1: 2338015 (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	Oct 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002617.4:c.820A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002608.1:p.Thr274Ala	missense
NM_001374425.1:c.877A>G	NP_001361354.1:p.Thr293Ala	missense
NM_001374426.1:c.445A>G	NP_001361355.1:p.Thr149Ala	missense
NM_001374427.1:c.388A>G	NP_001361356.1:p.Thr130Ala	missense
NM_153818.2:c.880A>G	NP_722540.1:p.Thr294Ala	missense
NR_164636.1:n.935A>G		non-coding transcript variant
NC_000001.11:g.2406576T>C
NC_000001.10:g.2338015T>C
NG_008342.1:g.10996A>G
NG_016128.1:g.19802T>C

... more HGVS ... less HGVS

Protein change

T294A, T274A, T130A, T149A, T293A

Other names

Canonical SPDI

NC_000001.11:2406575:T: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.

0.00859 (C)

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

1000 Genomes Project 30x 0.00843

1000 Genomes Project 0.00859

Trans-Omics for Precision Medicine (TOPMed) 0.01818

The Genome Aggregation Database (gnomAD) 0.01899

Exome Aggregation Consortium (ExAC) 0.01908

The Genome Aggregation Database (gnomAD), exomes 0.02025

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02091

Links

ClinGen: CA203142 dbSNP: rs34154371 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.
PEX10		-	-	GRCh38 GRCh37	770	933

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.
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Mar 29, 2016	RCV000179027.15
Peroxisome biogenesis disorder, complementation group 7	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000538777.8
Peroxisome biogenesis disorder 6A (Zellweger)	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Apr 27, 2017	RCV001097465.6
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Oct 1, 2020	RCV001540800.3
Zellweger spectrum disorders	Benign (1)	no assertion criteria provided	Nov 26, 2019	RCV001832028.1

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000316395.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Mar 29, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540015.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13006=2% (less) Method: Genome/Exome Filtration
Benign (Nov 23, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231216.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX10 Number of individuals with the variant: 1 Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Peroxisome biogenesis disorder, complementation group 7 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000644952.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Peroxisome biogenesis disorder 6A (Zellweger) Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001253747.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 15542397‚ 19127411 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Peroxisome biogenesis disorder 6A (Zellweger) (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435278.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This … (more) The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This variant has been identified in >2% of European (non-Finnish) chromosomes and 36 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Zellweger syndrome. (less)
Benign (Oct 01, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001758726.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 15542397, 27535533, 19127411)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005259196.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743100.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932171.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Nov 26, 2019)	no assertion criteria provided Method: clinical testing	Zellweger syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094106.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13006=2%

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This variant has been identified in >2% of European (non-Finnish) chromosomes and 36 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Zellweger syndrome.

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
A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts.	Steinberg SJ	Journal of inherited metabolic disease	2009	PMID: 19127411
The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum.	Steinberg S	Molecular genetics and metabolism	2004	PMID: 15542397
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX10	-	-	-	-

Text-mined citations for rs34154371 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002617.4(PEX10):c.820A>G (p.Thr274Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34154371 ...