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Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Classified gene: KIRREL3 as Green List (high evidence)
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Added comment: 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.
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Gene: kirrel3 has been classified as Green List (High Evidence).
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram 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.
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram 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
Intellectual disability v9.132 KIRREL3 Achchuthan Shanmugasundram Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Intellectual disability v9.130 KIRREL3 Achchuthan Shanmugasundram edited their review of gene: KIRREL3: Added comment: 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/).; Changed rating: RED; Changed publications to: 19012874, 29271092, 32503885, 37007974
Intellectual disability v7.43 KIRREL3 Arina Puzriakova Tag gene-checked tag was added to gene: KIRREL3.
Intellectual disability v7.41 KIRREL3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: KIRREL3.
Intellectual disability v7.41 KIRREL3 Achchuthan Shanmugasundram reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.40 KIRREL3 Achchuthan Shanmugasundram 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)
Intellectual disability v5.479 KIRREL3 Arina Puzriakova Added comment: 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.
Intellectual disability v5.479 KIRREL3 Arina Puzriakova Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Intellectual disability v5.442 KIRREL3 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: KIRREL3.
Intellectual disability v5.442 KIRREL3 Sarah Leigh Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947
Intellectual disability v5.441 KIRREL3 Sarah Leigh changed review comment from: At least 15 missense KIRREL3 variants have been reported in 17 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 19012874; 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, lists KIRREL3 variants and demonstrates that the variants maybe either de novo (9/16) or inherited from one of the parents (7/9). (PMID: 37605258). The KIRREL3 variants are either absent from control databases or are present at a very low frequency.; to: 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).
Intellectual disability v5.441 KIRREL3 Sarah Leigh Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability v5.441 KIRREL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.441 KIRREL3 Sarah Leigh Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.440 KIRREL3 Sarah Leigh reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29271092; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.440 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092; 37605258
Intellectual disability v5.439 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092:37605258
Intellectual disability v5.438 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 37605258
Intellectual disability v5.437 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 33853164; 37605258
Intellectual disability v5.436 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164
Intellectual disability v5.435 KIRREL3 Sarah Leigh Mode of inheritance for gene: KIRREL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.401 KIRREL3 Dmitrijs Rots reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37605258; Phenotypes: NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1349 KIRREL3 Ivone Leong Added comment: Comment on publications: New publication added (PMID:33853164)
Intellectual disability v3.1349 KIRREL3 Ivone Leong Publications for gene: KIRREL3 were set to 22965935; 19012874
Intellectual disability v3.1306 KIRREL3 Aleš Maver reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33853164; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.421 KIRREL3 Arina Puzriakova Source Expert Review Red was added to KIRREL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.253 KIRREL3 Arina Puzriakova commented on gene: KIRREL3
Intellectual disability v3.0 KIRREL3 Zornitza Stark reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: 19012874; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.490 KIRREL3 Louise Daugherty Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability v2.490 KIRREL3 Louise Daugherty Added comment: 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.
Intellectual disability v2.490 KIRREL3 Louise Daugherty Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.468 KIRREL3 Louise Daugherty Source Victorian Clinical Genetics Services was added to KIRREL3.
Intellectual disability KIRREL3 BRIDGE consortium edited their review of KIRREL3
Intellectual disability KIRREL3 BRIDGE consortium edited their review of KIRREL3
Intellectual disability KIRREL3 BRIDGE consortium reviewed KIRREL3