VCV000557980.10 - ClinVar

NM_000286.3(PEX12):c.987_988del (p.Phe330fs)

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.

(4)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000286.3(PEX12):c.987_988del (p.Phe330fs)

Variation ID: 557980 Accession: VCV000557980.10

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 17q12 17: 35575874-35575875 (GRCh38) [ NCBI UCSC ] 17: 33902893-33902894 (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	Aug 5, 2018	Jun 17, 2024	Jan 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000286.3:c.987_988del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000277.1:p.Phe330fs	frameshift
NM_000286.2:c.987_988del
NC_000017.11:g.35575875CA[2]
NC_000017.10:g.33902894CA[2]
NG_008447.1:g.7759GT[2]

... more HGVS ... less HGVS

Protein change

F330fs

Other names

Canonical SPDI

NC_000017.11:35575873:ACACACA:ACACA

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

dbSNP: rs764657253 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.
Peroxisome biogenesis disorder 3A (Zellweger) Peroxisome biogenesis disorder type 3B	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2018	RCV000674189.1
Peroxisome biogenesis disorder 3A (Zellweger)	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 23, 2024	RCV001239384.8
Peroxisome biogenesis disorder	Likely pathogenic (1)	criteria provided, single submitter	Mar 30, 2023	RCV003226365.1

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.
Uncertain significance (Apr 19, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Peroxisome biogenesis disorder type 3B Peroxisome biogenesis disorder 3A (Zellweger) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799481.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Likely pathogenic (Mar 30, 2023)	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: SCV003922616.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Comment: Variant summary: PEX12 c.987_988delGT (p.Phe330SerfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known … (more) Variant summary: PEX12 c.987_988delGT (p.Phe330SerfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Variants downstream of this position have been cited as pathogenic and disease-associated in ClinVar and HGMD and have been reported in affected individuals (PMIDs: 15542397, 33123925). The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.987_988delGT in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Dec 13, 2023)	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: SCV001412257.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Comment: This sequence change creates a premature translational stop signal (p.Phe330Serfs23) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Phe330Serfs23) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs764657253, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PEX12-related conditions. ClinVar contains an entry for this variant (Variation ID: 557980). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Gln337*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peroxisome biogenesis disorder 3A (Zellweger) Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201439.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

Variant summary: PEX12 c.987_988delGT (p.Phe330SerfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Variants downstream of this position have been cited as pathogenic and disease-associated in ClinVar and HGMD and have been reported in affected individuals (PMIDs: 15542397, 33123925). The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.987_988delGT in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Phe330Serfs*23) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs764657253, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PEX12-related conditions. ClinVar contains an entry for this variant (Variation ID: 557980). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Gln337*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs764657253 ...

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_000286.3(PEX12):c.987_988del (p.Phe330fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs764657253 ...