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Intellectual disability
Gene: KIRREL3

KIRREL3 (kirre like nephrin family adhesion molecule 3)
EnsemblGeneIds (GRCh38): ENSG00000149571
EnsemblGeneIds (GRCh37): ENSG00000149571
OMIM: 607761, Gene2Phenotype
KIRREL3 is in 2 panels

12 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Red List (low evidence)

Comment on list classification: As the evidence for the association of KIRREL3 gene with neurodevelopmental disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Created: 17 Oct 2025, 9:41 a.m. | Last Modified: 17 Oct 2025, 9:41 a.m.

Panel Version: 9.134

Monoallelic variants in KIRREL3 gene have been associated with complex neurodevelopmental disorder (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005235)

ClinGen curation reported the reason for 'Disputed' rating as below:
To date, over 20 probands (PMIDs: 29271092, 32503885, 37007974) with KIRREL3 truncating or missense variants and complex neurodevelopmental disorder have been reported. However, none of the missense variants were scored due to their presence in gnomAD and/or inheritance from reportedly unaffected parents and a lack of evidence of pathogenicity. Although three truncating variants were reported, KIRREL3 is not constrained for truncating variants (pLI = 0, gnomAD v4.0.0) or missense variants (Z = 1.59). Hence, the truncating variants were also not scored. Although functional in vitro studies of five KIRREL3 missense variants observed in affected individuals showed decreased synapse formation in hippocampal neurons, and studies in homozygous null Kirrel3-/- mice and synapse deficits in cultured Kirrel3+/- mouse hippocampal neurons suggest that KIRREL3 plays a role in central nervous system development, none of the experimental evidence was scored due to the lack of compelling genetic evidence.

Small variants in this gene have not been associated with any phenotypes ion OMIM (record accessed on 17 October 2025). This gene is also associated with 'limited' rating on the DD panel of Gene2Phenotype and with red rating on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia (https://panelapp-aus.org/panels/250/gene/KIRREL3/)
Created: 17 Oct 2025, 9:36 a.m. | Last Modified: 17 Oct 2025, 9:36 a.m.

Panel Version: 9.130

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Created: 26 Sep 2024, 2:57 p.m. | Last Modified: 26 Sep 2024, 2:57 p.m.

Panel Version: 7.41

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Created: 26 Sep 2024, 2:57 p.m.
Last Modified: 26 Sep 2024, 2:57 p.m.
Panel version: 9.130

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 5 Feb 2024, 4:46 p.m. | Last Modified: 5 Feb 2024, 4:46 p.m.

Panel Version: 5.441

At least 12 missense KIRREL3 variants have been reported in 12 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, reviews KIRREL3 variants and demonstrates that the variants maybe either de novo (4/11) or inherited from one of the parents (7/11)(mode of inheritance was unknown for one of the variants). The KIRREL3 variants are either absent from controls or are present at a very low frequency. However, the three variants reported in PMID: 19012874, were shown to be present in publicly databases at a high frequency (see KIRREL3 OMIM entry).
Created: 5 Feb 2024, 4:44 p.m. | Last Modified: 5 Feb 2024, 5:07 p.m.

Panel Version: 5.441

Publications

29271092

Created: 5 Feb 2024, 4:44 p.m.
Last Modified: 5 Feb 2024, 5:07 p.m.
Panel version: 5.440

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

21 reported case with mostly de novo, missense variants in PMID: 37605258. Enough evidence for the green rating!
Created: 16 Jan 2024, 12:30 p.m. | Last Modified: 16 Jan 2024, 12:30 p.m.

Panel Version: 5.401

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
NDD

Publications

PMID: 37605258

Created: 16 Jan 2024, 12:30 p.m.
Last Modified: 16 Jan 2024, 12:30 p.m.
Panel version: 5.401

Ivone Leong (Genomics England Curator)

Comment on publications: New publication added (PMID:33853164)
Created: 11 Oct 2021, 1:22 p.m. | Last Modified: 11 Oct 2021, 1:22 p.m.

Panel Version: 3.1349

Created: 11 Oct 2021, 1:22 p.m.
Last Modified: 11 Oct 2021, 1:22 p.m.
Panel version: 3.1349

Aleš Maver (Clinical Institute of Medical Genetics)

Red List (low evidence)

A de novo missense variant in KIRREL3 gene has been reported in a patient with NDD and cerebellar hypoplasia (p.Ser255Leu, PMID: 33853164). However, the same variant is also reported in one gnomAD case and the region is flagged as problematic in gnomAD, thus the classification remains questionable.
Created: 28 Sep 2021, 10:26 a.m. | Last Modified: 28 Sep 2021, 10:26 a.m.

Panel Version: 3.1306

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

PMID: 33853164

Created: 28 Sep 2021, 10:26 a.m.
Last Modified: 28 Sep 2021, 10:26 a.m.
Panel version: 3.1306

Arina Puzriakova (Genomics England Curator)

Comment on publications: New publication added - PMID:25902260. This paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques

Provides review of cases in literature and functional studies demonstrating brain expressed proteins that interact with the KIRREL3 using yeast two-hybrid screening supporting a link to neurological and cognitive disorders. They also show KIRREL3 localisation to the Golgi complex and synaptic secretary vesicles.
Created: 1 Mar 2024, 2:46 p.m. | Last Modified: 1 Mar 2024, 2:46 p.m.

Panel Version: 5.479

Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Created: 17 Aug 2020, 10:09 a.m. | Last Modified: 17 Aug 2020, 10:09 a.m.

Panel Version: 3.253

Created: 17 Aug 2020, 10:09 a.m.
Last Modified: 17 Aug 2020, 10:09 a.m.
Panel version: 3.253

Zornitza Stark (Australian Genomics)

Red List (low evidence)

Variants associated with ID have now been re-classified based on population frequency.
Created: 8 Feb 2020, 10:06 a.m. | Last Modified: 8 Feb 2020, 10:06 a.m.

Panel Version: 3.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability

Publications

19012874

Created: 8 Feb 2020, 10:06 a.m.
Last Modified: 8 Feb 2020, 10:06 a.m.
Panel version: 3.0

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), 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: 29 Sep 2018, 9:34 p.m.

Created: 29 Sep 2018, 9:34 p.m.

Panel version: 2.490

Olivia Niblock (Genomics England Curator)

I don't know

Amber - There are two human cases in the literature linking deletions of or variants in this gene to Intellectual disability. One paper describes a small interstitial deletion of 2.899Mb which encompasses this gene as a candidate. The patient presented with developmental delay and autistic features (PMID: 22965935). The other paper desricbes a patient with profound intellectual disability with a truncation of two genes - KIRREL3 and CDH15 - as a result of a translocation (19012874). Not able to distinguish whether or not this may be a digenic affect or solely due to transloaction of KIRREL3.
Created: 13 Dec 2017, 10:16 p.m.

Mode of inheritance
Unknown

Publications

Created: 13 Dec 2017, 10:16 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.5

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4)

Publications

19012874

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_2_4_2017;in_gilissen_2014_known . Main mutation mechanism : Uncertain
Created: 27 Jul 2017, 7:07 p.m.

Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; find_uk10k; gilissen_2014_known; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Uncertain. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:44 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Created: 2 Aug 2017, 7:49 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:08 a.m.

Panel version: 0.306

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
NHS GMS
Victorian Clinical Genetics Services
Radboud University Medical Center, Nijmegen

Phenotypes

complex neurodevelopmental disorder, MONDO:0100038

Tags

Q3_25_expert_review gene-checked disputed Q3_25_demote_red

OMIM

607761

Clinvar variants

Variants in KIRREL3

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

17 Oct 2025, Gel status: 3

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: kirrel3 has been classified as Green List (High Evidence).

17 Oct 2025, Gel status: 3

Added Tag, Added Tag, Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: KIRREL3. Tag disputed tag was added to gene: KIRREL3. Tag Q3_25_demote_red tag was added to gene: KIRREL3.

17 Oct 2025, Gel status: 3

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: KIRREL3 were changed from Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947 to complex neurodevelopmental disorder, MONDO:0100038

17 Oct 2025, Gel status: 3

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164

2 Oct 2024, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag gene-checked tag was added to gene: KIRREL3.

26 Sep 2024, Gel status: 3

Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q1_24_promote_green was removed from gene: KIRREL3.

26 Sep 2024, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source NHS GMS was added to KIRREL3. Source Expert Review Green was added to KIRREL3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

1 Mar 2024, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164

5 Feb 2024, Gel status: 2