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Primary immunodeficiency

Gene: UNC13D

Green List (high evidence)

UNC13D (unc-13 homolog D)
EnsemblGeneIds (GRCh38): ENSG00000092929
EnsemblGeneIds (GRCh37): ENSG00000092929
OMIM: 608897, Gene2Phenotype
UNC13D is in 7 panels

5 reviews

Eleanor Williams (Genomics England Curator)

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Created: 14 Oct 2020, 4:46 p.m. | Last Modified: 14 Oct 2020, 4:46 p.m.
Panel Version: 2.331
The following PubMed IDs were added to entity UNC13D: 27914778;14622600;17993578;29312353. These publications have been associated with OMIM phenotype MIM#608898, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.
Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.
Panel Version: 2.208

Publications

Kimberly Gilmour (Great Ormond Street Hopsital)

Green List (high evidence)

agree with green gene
Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94

Tracy Briggs (Manchester Genomic Medicine Centre)

Green List (high evidence)

YES- this is covered on our targeted exome
Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94

Sophie Hambleton (Newcastle University)

Green List (high evidence)

Louise Daugherty (Genomics England Curator)

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): UNC13D .PanelApp HGNC gene symbol check: UNC13D . IUIS Disease: UNC13D / Munc13-4 deficiency (FHL3) . IUIS Inheritance: AR , .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Fever, HSM, HLH, cytopenias, . IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes)
Created: 2 Jul 2018, 10:35 a.m.
Comment on list classification: Changed status from Amber to Green, there are more than 3 unrelated cases to support the phenotype Familial hemophagocytic lymphohistiocytosis-3 (FHL3) caused by homozygous or compound heterozygous mutation in the gene encoding perforin UNC13D
Created: 30 Apr 2018, 11:36 a.m.
from GeneReview PMID:20301617: Approx 20%-30% 3, 5 worldwide of FHL are FHL3 (Hemophagocytic lymphohistiocytosis, familial, 3) PMID:15632205, PMID:15703195.
Created: 30 Apr 2018, 11:33 a.m.
Comment on publications: added publication PMID: 17993578 to support age-specific-variation tag eg: this gene is not specific to early onset
Created: 30 Apr 2018, 11:30 a.m.
Added age-specific-variation tag
Created: 30 Apr 2018, 11:28 a.m.
from OMIM: Feldmann et al. (2003) PMID: 14622600 Identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with Hemophagocytic lymphohistiocytosis-3 (FHL3). In a Turkish patient from a consanguineous family with primary hemophagocytic lymphohistiocytosis, Zur Stadt et al. (2006) PMID:16278825 identified homozygosity for a missense mutation in the UNC13D gene.
Rudd et al. (2008) PMID: 17993578 reported 9 patients from 6 families with genetically confirmed FHL3. There was considerable variation in age at diagnosis, ranging from birth to 14 years, and 3 of the 9 mutation-positive patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was evident in the 2 patients investigated, and was more pronounced in the patient with onset during infancy than in the patient with adolescent onset.
Created: 30 Apr 2018, 11:26 a.m.
Comment on publications: Added publications to support role of UNC13D variants in Hemophagocytic lymphohistiocytosis, familial, 3
Created: 30 Apr 2018, 11:22 a.m.
Comment on phenotypes: added OMIM MIMid and synonyms
Created: 30 Apr 2018, 11:17 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: 19 Apr 2018, 10:55 a.m.
Original metadata downloaded from ESID Registry. ESID_Gene_original: UNC13D, PanelApp HGNC gene symbol check: UNC13D, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Hemophagocytic Lymphohistiocytosis (HLH) / Familial hemophagocytic lymphohistiocytosis syndromes (FHLH)
Created: 17 Apr 2018, 12:29 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: UNC13D, GRID_Gene_Symbol: UNC13D, GRID_Transcript_ENS_Community submitted: ENST00000207549, GRID_Transcript_RefSeq: NM_199242.2, GRID_Transcript_ENS_used_on_Production: ENST00000207549
Created: 17 Apr 2018, 12:12 p.m.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
  • NHS GMS
  • North West GLH
  • London North GLH
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • ESID Registry 20171117
  • GRID V2.0
  • GOSH PID v.8.0
Phenotypes
  • Hemophagocytic lymphohistiocytosis, familial 3, 608898
  • FHL3
  • Familial hemophagocytic lymphohistiocytosis syndromes (FHLH)
  • HPLH3
  • HLH3
  • Fever, HSM, HLH, cytopenias,
  • Diseases of Immune Dysregulation
Tags
age-specific-variation
OMIM
608897
Clinvar variants
Variants in UNC13D
Penetrance
None
Publications
Panels with this gene

History Filter Activity

14 Oct 2020, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: unc13d has been classified as Green List (High Evidence).

13 Oct 2020, Gel status: 1

Added New Source, Set publications, Status Update

Eleanor Williams (Genomics England Curator)

Source Other was added to UNC13D. Publications for gene UNC13D were updated from 14622600; 16278825; 15632205; 17993578; 15703195 to 15703195; 16278825; 17993578; 27914778; 15632205; 14622600; 29312353 Rating Changed from Green List (high evidence) to Red List (low evidence)

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to UNC13D.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source North West GLH was added to UNC13D.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to UNC13D.

12 Jul 2018, Gel status: 4

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.

1 Jul 2018, Gel status: 4

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene UNC13D were set to Hemophagocytic lymphohistiocytosis, familial 3, 608898, FHL3, Familial hemophagocytic lymphohistiocytosis syndromes (FHLH), HPLH3, HLH3, Fever, HSM, HLH, cytopenias,, Diseases of Immune Dysregulation

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to UNC13D. Panel: Primary immunodeficiency disorders

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Victorian Clinical Genetics Services was added to UNC13D. Panel: Primary immunodeficiency disorders

13 Jun 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: unc13d has been classified as Green List (High Evidence).

30 Apr 2018, Gel status: 3

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

30 Apr 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for UNC13D were set to 14622600; 16278825; 15632205; 17993578; 15703195

30 Apr 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for UNC13D were set to 14622600; 16278825; 15632205; 17993578

30 Apr 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for UNC13D were set to 14622600; 16278825; 15632205

30 Apr 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for UNC13D were set to Hemophagocytic lymphohistiocytosis, familial 3, 608898; FHL3; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH3; HLH3

30 Apr 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for UNC13D were set to Hemophagocytic lymphohistiocytosis, familial 3, 608898; FHL3; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH3; HLH3

19 Apr 2018, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

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

17 Apr 2018, Gel status: 1

Added New Source, Set penetrance

Louise Daugherty (Genomics England Curator)

ESID Registry 20171117 was added to UNC13D. Panel: Primary immunodeficiency disorders Phenotypes for gene UNC13D were set to Hemophagocytic lymphohistiocytosis, familial, 3, Familial hemophagocytic lymphohistiocytosis syndromes (FHLH)

17 Apr 2018, Gel status: 1

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene UNC13D were set to Hemophagocytic lymphohistiocytosis, familial, 3

17 Apr 2018, Gel status: 1

Added New Source, Set mode of inheritance, Set penetrance

Louise Daugherty (Genomics England Curator)

GRID V2.0 was added to UNC13D. Panel: Primary immunodeficiency disorders Model of inheritance for gene UNC13D was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene UNC13D were set to Hemophagocytic lymphohistiocytosis, familial, 3

6 Apr 2018, Gel status: 1

Clear Sources

Louise Daugherty (Genomics England Curator)

UNC13D Source: GOSH PID 20171205 was removed from gene: UNC13D

6 Apr 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

GOSH PID v.8.0 was added to UNC13D. Panel: Primary immunodeficiency disorders

29 Mar 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

UNC13D was added to Primary immunodeficiency disorders panel. Sources: GOSH PID 20171205

29 Mar 2018, Gel status: 1

Created

Louise Daugherty (Genomics England Curator)

UNC13D was created by Louise Daugherty