VCV000092773.37 - ClinVar

NM_000286.3(PEX12):c.102A>T (p.Arg34Ser)

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.

(14)

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_000286.3(PEX12):c.102A>T (p.Arg34Ser)

Variation ID: 92773 Accession: VCV000092773.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q12 17: 35577920 (GRCh38) [ NCBI UCSC ] 17: 33904939 (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	Jun 28, 2015	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000286.3:c.102A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000277.1:p.Arg34Ser	missense
NC_000017.11:g.35577920T>A
NC_000017.10:g.33904939T>A
NG_008447.1:g.5718A>T
	O00623:p.Arg34Ser

... more HGVS ... less HGVS

Protein change

R34S

Other names

Canonical SPDI

NC_000017.11:35577919:T:A

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.

0.00220 (A)

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

1000 Genomes Project 0.00220

1000 Genomes Project 30x 0.00234

Trans-Omics for Precision Medicine (TOPMed) 0.00365

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00492

The Genome Aggregation Database (gnomAD) 0.00493

The Genome Aggregation Database (gnomAD), exomes 0.00573

Exome Aggregation Consortium (ExAC) 0.00574

Links

dbSNP: rs147530802 ClinGen: CA145995 UniProtKB: O00623#VAR_058389 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.
PEX12		-	-	GRCh38 GRCh37	513	525

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 (5)	criteria provided, multiple submitters, no conflicts	Jun 14, 2022	RCV000078560.22
Peroxisome biogenesis disorder type 3B	Benign (1)	criteria provided, single submitter	May 28, 2019	RCV000989844.9
Peroxisome biogenesis disorder 3A (Zellweger)	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001082581.20
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV000514867.25
PEX12-related disorder	Likely benign (1)	no assertion criteria provided	Feb 14, 2020	RCV004549498.2
Peroxisome biogenesis disorder 3A (Zellweger) Peroxisome biogenesis disorder type 3B	Likely benign (1)	criteria provided, single submitter	Apr 12, 2022	RCV002498379.8

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.
Likely benign (Mar 28, 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: SCV000540016.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	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: Benign by Emory 2014. Has been reported in 2 homozygous individuals of iranian origin, who presented with peroxisomal biogenesis disorder with mild clinical phenotype. Consanguinity in at least one of the families. (Zeharia 2007). Given the high frequency in ExAC, LB (less) Method: Genome/Exome Filtration
Benign (Sep 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610365.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Benign (May 02, 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: SCV000110416.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX12 Number of individuals with the variant: 4 Sex: mixed
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Peroxisome biogenesis disorder type 3B Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140435.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Peroxisome biogenesis disorder 3A (Zellweger) Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001284750.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 17534573‚ 15542397 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 (Jun 14, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002555864.1 First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022	Comment: Variant summary: PEX12 c.102A>T (p.Arg34Ser) results in a non-conservative amino acid change located in the Pex, N-terminal domain (IPR006845) of the encoded protein sequence. Four … (more) Variant summary: PEX12 c.102A>T (p.Arg34Ser) results in a non-conservative amino acid change located in the Pex, N-terminal domain (IPR006845) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0058 in 282832 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX12 causing Zellweger Syndrome (0.0016), strongly suggesting that the variant is benign. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and four as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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: SCV005214665.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Dec 09, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001831033.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: This variant is associated with the following publications: (PMID: 26643206, 17534573, 15542397)
Likely benign (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peroxisome biogenesis disorder type 3B Peroxisome biogenesis disorder 3A (Zellweger) Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808579.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Peroxisome biogenesis disorder 3A (Zellweger) Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001099586.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Jun 01, 2024)	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: SCV004144463.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: PEX12: BS1, BS2 Number of individuals with the variant: 6
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001927793.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (Feb 14, 2020)	no assertion criteria provided Method: clinical testing	PEX12-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004797104.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973842.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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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: Benign by Emory 2014. Has been reported in 2 homozygous individuals of iranian origin, who presented with peroxisomal biogenesis disorder with mild clinical phenotype. Consanguinity in at least one of the families. (Zeharia 2007). Given the high frequency in ExAC, LB

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:

Variant summary: PEX12 c.102A>T (p.Arg34Ser) results in a non-conservative amino acid change located in the Pex, N-terminal domain (IPR006845) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0058 in 282832 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX12 causing Zellweger Syndrome (0.0016), strongly suggesting that the variant is benign. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and four as benign. Based on the evidence outlined above, the variant was classified as 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
A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C.	Zeharia A	Journal of human genetics	2007	PMID: 17534573
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=PEX12	-	-	-	-

Text-mined citations for rs147530802 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000286.3(PEX12):c.102A>T (p.Arg34Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147530802 ...