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Primary immunodeficiency

Gene: POLE

Amber List (moderate evidence)

POLE (DNA polymerase epsilon, catalytic subunit)
EnsemblGeneIds (GRCh38): ENSG00000177084
EnsemblGeneIds (GRCh37): ENSG00000177084
OMIM: 174762, Gene2Phenotype
POLE is in 10 panels

6 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Created: 20 Oct 2020, 3:19 p.m. | Last Modified: 20 Oct 2020, 3:19 p.m.
Panel Version: 2.347

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Amber to Green following review by Zornitza Stark: >3 cases from 3 separate papers of individuals with biallelic POLE variants and a phenotype that includes immunodeficiency.
Created: 29 Apr 2020, 4:58 p.m. | Last Modified: 29 Apr 2020, 4:58 p.m.
Panel Version: 2.134
PMID:23230001: 1 large consanguineous family with FILS syndrome (all but 2 patients suffered from immunodeficiency) and homozygous single bp substitution in POLE1.
Created: 29 Apr 2020, 4:57 p.m. | Last Modified: 29 Apr 2020, 7:58 p.m.
Panel Version: 2.134
PMID:25948378 (Thiffault et al., 2015) report a girl with immune deficiency amongst her phenotypes. She was homozygous for a splice variant in POLE1 (c.4444 + 3A > G).
Created: 29 Apr 2020, 4:56 p.m. | Last Modified: 29 Apr 2020, 4:56 p.m.
Panel Version: 2.133
PMID:30503519 (Logan et al., 2018) report biallelic variants in POLE in 15 indivs from 12 families (mix of countries). All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. Phenotypically, affected individuals all had IUGR and severe growth failure of prenatal onset. Immunodeficiency in 9 families (either increased susceptibility to infections or documented lymphopenia/ hypogammaglobinemia).
Created: 29 Apr 2020, 4:33 p.m. | Last Modified: 29 Apr 2020, 4:33 p.m.
Panel Version: 2.133

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Both the FILS and IMAGE-I phenotypes have immunodeficiency as a feature. Note recurrent intronic variant, c.1686+32C-G (intron 15) in IMAGE-I, found in combination with multiple other variants.
Created: 11 Apr 2020, 5:08 a.m. | Last Modified: 11 Apr 2020, 5:08 a.m.
Panel Version: 2.51

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
FILS syndrome, MIM# 615139; IMAGE-I syndrome, MIM# 618336

Publications

Sophie Hambleton (Newcastle University)

I don't know

Only one family described
Created: 29 Jun 2018, 3:05 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Sarah Leigh (Genomics England Curator)

Comment on list classification: Associated with phenotypes in OMIM and as a probable Gen2Phen gene for {Colorectal cancer, susceptibility to, 12} 615083. At least 1 variant identified in affected members of a single family with FILS syndrome 615139. Supportive in vitro studies also presented (PMID 23230001)
Created: 9 May 2018, 12:57 p.m.
Comment on phenotypes: Autosomal dominant variants also associated with {Colorectal cancer, susceptibility to, 12} 615083.
Created: 9 May 2018, 12:41 p.m.

Louise Daugherty (Genomics England Curator)

I don't know

Keep Amber until more info on gene and disease association regarding immunological phenotype. Only one family reported but with supportive in vitro studies . Request evidences from GRID and Victorian Clinical Genetics Services
Created: 4 Jul 2018, 5:55 p.m.
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): POLE .PanelApp HGNC gene symbol check: POLE . IUIS Disease: POLE1 (Polymerase _ subunit 1) deficiency (FILS syndrome) . IUIS Inheritance: AR .T cells: Low CD4 cells, .B cells: Low memory B cells, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature . IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: DNA Repair Defects other than those listed in Table 1
Created: 2 Jul 2018, 10:35 a.m.
This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.
Created: 20 Apr 2018, 12:25 p.m.
Original metadata downloaded from ESID Registry. ESID_Gene_original: POLE1, PanelApp HGNC gene symbol check: POLE, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Other well defined PIDs / FILS syndrome / Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome)
Created: 17 Apr 2018, 12:29 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: POLE, GRID_Gene_Symbol: POLE, GRID_Transcript_ENS_Community submitted: ENST00000320574, GRID_Transcript_RefSeq: NM_006231.3, GRID_Transcript_ENS_used_on_Production: ENST00000320574
Created: 17 Apr 2018, 12:12 p.m.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • ESID Registry 20171117
  • GRID V2.0
Phenotypes
  • FILS syndrome 615139
  • Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome)
  • Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature
  • Combined immunodeficiencies with associated or syndromic features
Tags
for-review
OMIM
174762
Clinvar variants
Variants in POLE
Penetrance
None
Publications
Panels with this gene

History Filter Activity

20 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: pole has been classified as Amber List (Moderate Evidence).

20 Oct 2020, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: POLE.

29 Apr 2020, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: pole has been classified as Green List (High Evidence).

12 Jul 2018, Gel status: 2

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.

4 Jul 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: pole has been classified as Amber List (Moderate Evidence).

1 Jul 2018, Gel status: 2

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene POLE were set to FILS syndrome 615139, Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome), Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature, Combined immunodeficiencies with associated or syndromic features

26 Jun 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to POLE. Panel: Primary immunodeficiency disorders

26 Jun 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Victorian Clinical Genetics Services was added to POLE. Panel: Primary immunodeficiency disorders

9 May 2018, Gel status: 2

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

9 May 2018, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for POLE were set to 23230001

9 May 2018, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for POLE were set to FILS syndrome 615139; Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome)

20 Apr 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Expert Review Amber was added to POLE. Panel: Primary immunodeficiency disorders

17 Apr 2018, Gel status: 1

Added New Source, Set penetrance

Louise Daugherty (Genomics England Curator)

ESID Registry 20171117 was added to POLE. Panel: Primary immunodeficiency disorders Phenotypes for gene POLE were set to FILS syndrome, Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome)

17 Apr 2018, Gel status: 1

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene POLE were set to FILS syndrome

17 Apr 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

POLE was added to Primary immunodeficiency disorders panel. Sources: GRID V2.0

17 Apr 2018, Gel status: 1

Created

Louise Daugherty (Genomics England Curator)

POLE was created by Louise Daugherty