NM_000287.4(PEX6):c.2362G>A (p.Val788Met) AND Peroxisome biogenesis disorder

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 2, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000780591.10

Allele description [Variation Report for NM_000287.4(PEX6):c.2362G>A (p.Val788Met)]

NM_000287.4(PEX6):c.2362G>A (p.Val788Met)

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.2362G>A (p.Val788Met)

HGVS:

NC_000006.12:g.42966044C>T
NG_008370.1:g.18200G>A
NM_000287.4:c.2362G>AMANE SELECT
NM_001316313.2:c.2098G>A
NP_000278.3:p.Val788Met
NP_001303242.1:p.Val700Met
NC_000006.11:g.42933782C>T
NM_000287.3:c.2362G>A

Protein change:

V700M

Links:

dbSNP: rs267608240

NCBI 1000 Genomes Browser:

rs267608240

Molecular consequence:

NM_000287.4:c.2362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316313.2:c.2098G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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alpha-2-macroglobulin family protein, partial [Alistipes shahii]
alpha-2-macroglobulin family protein, partial [Alistipes shahii]
gi|2594346181|ref|WP_316929184.1|

Protein
lipopolysaccharide assembly protein LapB [Alistipes sp. AF14-19]
lipopolysaccharide assembly protein LapB [Alistipes sp. AF14-19]
gi|2294390453|ref|WP_259301966.1|

Protein
Homo sapiens von Willebrand factor A domain containing 5B1 (VWA5B1), transcript ...
Homo sapiens von Willebrand factor A domain containing 5B1 (VWA5B1), transcript variant 1, mRNA
gi|1531792015|ref|NM_001039500.3|

Nucleotide
Trigeminal Nuclei
Trigeminal Nuclei
Nuclei of the trigeminal nerve situated in the brain stem. They include the nucleus of the spinal trigeminal tract (TRIGEMINAL NUCLEUS, SPINAL), the principal sensory nucleus,...<br/>Year introduced: 1980

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000917988	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 31, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19142205, 15542397, 26700162, 19877282, 11355018 Citation Link,
SCV002132589	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 2, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 3515938, 19142205, 19877282, 26700162, 17576681, 9536098, 11355018, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000917988

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 31, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002132589

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 2, 2021)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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

The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum.

Steinberg S, Chen L, Wei L, Moser A, Moser H, Cutting G, Braverman N.

Mol Genet Metab. 2004 Nov;83(3):252-63.

PubMed [citation]

PMID:: 15542397

Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes.

Kelley RI, Datta NS, Dobyns WB, Hajra AK, Moser AB, Noetzel MJ, Zackai EH, Moser HW.

Am J Med Genet. 1986 Apr;23(4):869-901. Review.

PubMed [citation]

PMID:: 3515938

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917988.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: PEX6 c.2362G>A (p.Val788Met) results in a conservative amino acid change located in the ATPase, AAA-type, core domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is the last exonic nucleotide at an exon-intron junction, suggesting it may affect splicing. At least one publication, Matsumoto_2001, reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 1.6e-05 in 251656 control chromosomes (gnomAD). The variant, c.2362G>A, has been reported in the literature in multiple individuals affected with Zellweger Syndrome, both as a homozygous and compound heterozygous allele. (Steinberg_2004, Krause_2009, Ebberink_2010, Lusebrink_2016). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lusebrink_2016). One ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002132589.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces valine with methionine at codon 788 of the PEX6 protein (p.Val788Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of neonatal adrenoleukodystrophy or Zellweger syndrome (PMID: 3515938, 19142205, 19877282, 26700162). This variant is also known as PEX6del2095‚Äì2362/21ins. ClinVar contains an entry for this variant (Variation ID: 556244). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exons 11 and 12 and an insertion of 21 nucleotides, which introduces a frameshift and introduces a premature termination codon (PMID: 11355018). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Oct 20, 2024

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