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Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 ITPR3 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: ITPR3.
Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 ITPR3 Achchuthan Shanmugasundram commented on gene: ITPR3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Primary immunodeficiency or monogenic inflammatory bowel disease v7.25 ITPR3 Achchuthan Shanmugasundram Source NHS GMS was added to ITPR3.
Source Expert Review Green was added to ITPR3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v6.16 ITPR3 Achchuthan Shanmugasundram Classified gene: ITPR3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v6.16 ITPR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The availability of four unrelated cases reported with the same de novo dominant-negative variant and supporting functional studies for this variant provides sufficient evidence for monoallelic MOI.

The presence of two unrelated cases reported with compound heterozygous variants and supporting functional work provides sufficient evidence for biallelic MOI.

Hence, the MOI was set to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" and the gene has been recommended for promotion to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v6.16 ITPR3 Achchuthan Shanmugasundram Gene: itpr3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v6.15 ITPR3 Achchuthan Shanmugasundram Phenotypes for gene: ITPR3 were changed from Multisystemic to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v6.14 ITPR3 Achchuthan Shanmugasundram Publications for gene: ITPR3 were set to PMID: 39270020
Primary immunodeficiency or monogenic inflammatory bowel disease v6.13 ITPR3 Achchuthan Shanmugasundram edited their review of gene: ITPR3: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v6.13 ITPR3 Achchuthan Shanmugasundram Mode of inheritance for gene: ITPR3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v6.12 ITPR3 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: ITPR3.
Tag Q3_24_promote_green tag was added to gene: ITPR3.
Primary immunodeficiency or monogenic inflammatory bowel disease v6.12 ITPR3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ITPR3.
Primary immunodeficiency or monogenic inflammatory bowel disease v6.12 ITPR3 Achchuthan Shanmugasundram changed review comment from: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation.

PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.; to: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation.

PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.

Neither monoallelic nor biallelic variants in this gene has been associated with immunodeficiency phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v6.12 ITPR3 Achchuthan Shanmugasundram changed review comment from: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation.

PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that; to: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation.

PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v6.12 ITPR3 Achchuthan Shanmugasundram reviewed gene: ITPR3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 36302985, 39270020; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v6.4 ITPR3 Dmitrijs Rots gene: ITPR3 was added
gene: ITPR3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to PMID: 39270020
Phenotypes for gene: ITPR3 were set to Multisystemic
Mode of pathogenicity for gene: ITPR3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: ITPR3 was set to GREEN
Added comment: PMID: 39270020 Described 4 cases with the dame de novo variant and a complex phenotype including immunodeficiency + functional work. Enought for green rating
Sources: Literature