NM_000318.3(PEX2):c.354_355del (p.Arg119fs) AND Peroxisome biogenesis disorder 5A (Zellweger)

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 19, 2023
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:: RCV003472127.4

Allele description [Variation Report for NM_000318.3(PEX2):c.354_355del (p.Arg119fs)]

NM_000318.3(PEX2):c.354_355del (p.Arg119fs)

Gene:

PEX2:peroxisomal biogenesis factor 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8q21.13

Genomic location:

Preferred name:

NM_000318.3(PEX2):c.354_355del (p.Arg119fs)

HGVS:

NC_000008.11:g.76983824_76983825del
NG_008371.1:g.21464_21465del
NM_000318.2:c.354_355del
NM_000318.3:c.354_355delMANE SELECT
NM_001079867.2:c.354_355del
NM_001172086.2:c.354_355del
NM_001172087.2:c.354_355del
NP_000309.2:p.Arg119fs
NP_001073336.2:p.Arg119fs
NP_001165557.2:p.Arg119fs
NP_001165558.2:p.Arg119fs
NC_000008.10:g.77896060_77896061del
NM_000318.2:c.354_355delAC

Protein change:

R119fs

Links:

dbSNP: rs1554584505

NCBI 1000 Genomes Browser:

rs1554584505

Molecular consequence:

NM_000318.3:c.354_355del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079867.2:c.354_355del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001172086.2:c.354_355del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001172087.2:c.354_355del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Peroxisome biogenesis disorder 5A (Zellweger) (PBD5A)
Identifiers:: MONDO: MONDO:0013932; MedGen: C3553940; Orphanet: 912; OMIM: 614866

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004201488	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004470535	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004201488

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 19, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004470535

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 31, 2022)

germline

clinical testing

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	germline	unknown	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Baylor Genetics, SCV004201488.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004470535.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PEX2 protein in which other variant(s) (p.Leu207Serfs*10) 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. ClinVar contains an entry for this variant (Variation ID: 554942). This variant has not been reported in the literature in individuals affected with PEX2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg119Metfs*3) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acid(s) of the PEX2 protein.

#	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

Last Updated: Sep 29, 2024

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