VCV000556748.3 - ClinVar

NM_000287.4(PEX6):c.1238G>T (p.Gly413Val)

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.

(3)

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
Likely pathogenic(1); 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_000287.4(PEX6):c.1238G>T (p.Gly413Val)

Variation ID: 556748 Accession: VCV000556748.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.1 6: 42969797 (GRCh38) [ NCBI UCSC ] 6: 42937535 (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	Jul 15, 2024	Apr 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000287.4:c.1238G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000278.3:p.Gly413Val	missense
NM_001316313.2:c.974G>T	NP_001303242.1:p.Gly325Val	missense
NR_133009.2:n.1269G>T		non-coding transcript variant
NC_000006.12:g.42969797C>A
NC_000006.11:g.42937535C>A
NG_008370.1:g.14447G>T

... more HGVS ... less HGVS

Protein change

G413V, G325V

Other names

Canonical SPDI

NC_000006.12:42969796:C: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.

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

Links

OMIM: 601498.0016 dbSNP: rs1554127531 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.
PEX6		-	-	GRCh38 GRCh37	1751	1771

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 4A (Zellweger) Peroxisome biogenesis disorder 4B	Uncertain significance (1)	criteria provided, single submitter	Feb 15, 2018	RCV000672797.1
Heimler syndrome 2	Pathogenic (1)	no assertion criteria provided	Nov 25, 2020	RCV001268931.1
Peroxisome biogenesis disorder	Likely pathogenic (1)	criteria provided, single submitter	Apr 25, 2024	RCV004586868.1

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 (Feb 15, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Peroxisome biogenesis disorder 4A (Zellweger) Peroxisome biogenesis disorder 4B Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000797940.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 26593283
Likely pathogenic (Apr 25, 2024)	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: SCV005076508.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (1) PubMed: 26593283 Comment: Variant summary: PEX6 c.1238G>T (p.Gly413Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: PEX6 c.1238G>T (p.Gly413Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-07 in 1461712 control chromosomes (gnomAD v4.0.0). c.1238G>T has been reported in the literature in individuals affected with Peroxisome Biogenesis Disorder (Zaki_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26593283). ClinVar contains an entry for this variant (Variation ID: 556748). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Nov 25, 2020)	no assertion criteria provided Method: literature only	HEIMLER SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001448181.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Publications: PubMed (1) PubMed: 26593283 Comment on evidence: In 2 sibs, born to consanguineous Egyptian parents, with Heimler syndrome-2 (HMLR2; 616617), Zaki et al. (2016) identified a homozygous c.1238G-T transversion (c.1238G-T, NM_000287.3) in … (more) In 2 sibs, born to consanguineous Egyptian parents, with Heimler syndrome-2 (HMLR2; 616617), Zaki et al. (2016) identified a homozygous c.1238G-T transversion (c.1238G-T, NM_000287.3) in exon 5 of the PEX6 gene, resulting in a gly413-to-val (G413V) substitution at a conserved residue in the HBD domain. The mutation, which was found by genomewide linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The parents were confirmed to be carriers. Functional studies were not performed. (less)

Comment:

Variant summary: PEX6 c.1238G>T (p.Gly413Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-07 in 1461712 control chromosomes (gnomAD v4.0.0). c.1238G>T has been reported in the literature in individuals affected with Peroxisome Biogenesis Disorder (Zaki_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26593283). ClinVar contains an entry for this variant (Variation ID: 556748). Based on the evidence outlined above, the variant was classified as likely 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

Title	Author	Journal	Year	Link
PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly.	Zaki MS	Human mutation	2016	PMID: 26593283

Text-mined citations for rs1554127531 ...

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 Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000287.4(PEX6):c.1238G>T (p.Gly413Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554127531 ...