NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln) AND Peroxisome biogenesis disorder

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 23, 2024
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:: RCV001379858.8

Allele description [Variation Report for NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln)]

NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln)

Gene:

PEX6:peroxisomal biogenesis factor 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln)

HGVS:

NC_000006.12:g.42965717C>T
NG_008370.1:g.18527G>A
NG_008396.1:g.9956C>T
NM_000287.4:c.2435G>AMANE SELECT
NM_001316313.2:c.2171G>A
NP_000278.3:p.Arg812Gln
NP_001303242.1:p.Arg724Gln
NC_000006.11:g.42933455C>T
NM_000287.3:c.2435G>A
NR_133009.2:n.2219G>A
p.(Arg812Gln)

Protein change:

R724Q

Links:

dbSNP: rs61753229

NCBI 1000 Genomes Browser:

rs61753229

Molecular consequence:

NM_000287.4:c.2435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316313.2:c.2171G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_133009.2:n.2219G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Peroxisome biogenesis disorder (PBD, ZSS)
Synonyms:: PEROXISOME BIOGENESIS DISORDER (NEONATAL ADRENOLEUKODYSTROPHY/INFANTILE REFSUM DISEASE); INFANTILE PHYTANIC ACID STORAGE DISEASE; PEROXISOME BIOGENESIS DISORDER (NALD/IRD); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019234; MedGen: C1832200; OMIM: PS214100

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Plant sample from Cornus sanguinea
Plant sample from Cornus sanguinea

biosample
Limbic Lobe
Limbic Lobe
The medial surface of the cerebral hemisphere around the brain stem.<br/>Year introduced: 2015

MeSH
Substantia Innominata
Substantia Innominata
Tissue in the BASAL FOREBRAIN inferior to the anterior perforated substance, and anterior to the GLOBUS PALLIDUS and ansa lenticularis. It contains the BASAL NUCLEUS OF MEYNER...<br/>Year introduced: 1991(1984)

MeSH
Hypothalamus
Hypothalamus
Ventral part of the DIENCEPHALON extending from the region of the OPTIC CHIASM to the caudal border of the MAMMILLARY BODIES and forming the inferior and lateral walls of the ...<br/>

MeSH
Glymphatic System
Glymphatic System
A vascular waste clearance system in the brain analogous to the lymphatic system that facilitates transporting of solutes and waste products from CEREBROSPINAL FLUID (CSF) and...<br/>Year introduced: 2019

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577741	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10408779, 19877282, 28492532
SCV005076996	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 23, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19877282, 10408779 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577741

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005076996

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 23, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

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

Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.

Ebberink MS, Kofster J, Wanders RJ, Waterham HR.

Hum Mutat. 2010 Jan;31(1):E1058-70. doi: 10.1002/humu.21153.

PubMed [citation]

PMID:: 19877282

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577741.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 812 of the PEX6 protein (p.Arg812Gln). This variant is present in population databases (rs61753229, gnomAD 0.02%). This missense change has been observed in individuals with Zellweger syndrome (PMID: 10408779, 19877282). ClinVar contains an entry for this variant (Variation ID: 555170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX6 protein function. Experimental studies have shown that this missense change affects PEX6 function (PMID: 10408779). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg812 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 19877282), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005076996.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: PEX6 c.2435G>A (p.Arg812Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 1.2e-05 in 251484 control chromosomes. c.2435G>A has been reported in the literature in individuals affected with Zellweger Syndrome (e.g. Zhang_1999, Ebberink_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in the inability to rescue peroxisome biogenesis activity in deficient cells (Zhang_1999). The following publications have been ascertained in the context of this evaluation (PMID: 19877282, 10408779). ClinVar contains an entry for this variant (Variation ID: 555170). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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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