Submission Details

ITPR1 encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3) and is enriched in the brain, particularly in the Purkinje cells of the cerebellum. ITPR1 was first reported in relation to autosomal dominant spinocerebellar ataxia type 29 (SCA29) in 2012 (Huang et al., PMID: 22986007). Clinical features include cerebellar ataxia with onset in infancy or childhood, hypotonia, gross motor delay, oculomotor abnormalities, dysarthria, mild-to-moderate intellectual disability or learning disability, and cerebellar atrophy/hypoplasia. ITPR1 has also been reported in relation to autosomal dominant spinocerebellar ataxia type 15 (SCA15), an adult-onset, slowly progressive cerebellar ataxia. Heterozygous missense variants cause SCA29, while heterozygous loss-of-function variants, mainly deletions, cause SCA15. Based on the ClinGen Lumping and Splitting guidance, there are differences in molecular mechanism and phenotype and therefore, the two types of spinocerebellar ataxia were assessed separately. This curation concerns autosomal dominant SCA29. The relationship between ITPR1 and SCA15 will be curated separately by another gene curation expert panel.

This curation includes 9 missense variants that have been reported in 10 probands in 6 publications (PMIDs: 25794864, 27062503, 28620721, 29925855, 31632679), and segregation data in one large family (PMID: 22986007). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The variants are often de novo but may also be inherited from an affected parent, and many are recurrent. Most reported variants cluster in the N-terminal IP3 binding domain, the C-terminal channel domain and the CAR8-binding region (PMID: 37964426). SCA29 variants within or near the IP3-binding domain of IP3R1 (including hotspot variants p.Thr267Met and p.Arg269Trp) abolish IP3-induced Ca2+ channel activity and several also reduce IP3 binding, suggesting that the mechanism of pathogenicity is dominant-negative loss of function (PMID: 30429331). However, the SCA29 variant p.Arg36Cys, located in the suppressor domain, and two variants in the CAR8-binding region (p.Ser1502Asp and p.Val1562Met), exhibit increased IP3 binding and elevation of intracellular Ca2+ signal compared to wild-type ITPR1 (PMIDs: 28620721, 30429331), indicating that both gain and loss of function can lead to SCA29.

Of note, autosomal dominant and recessive forms of Gillespie syndrome, characterized by aniridia, cerebellar ataxia and intellectual disability, have been reported in relation to heterozygous missense variants in the C-terminal domain of ITPR1 or biallelic truncating variants, respectively. The relationship between ITPR1 and Gillespie syndrome was evaluated separately. No obvious genotype-phenotype correlations have been observed for the SCA29 and Gillespie syndrome variants clustered in the C-terminal domain (PMID: 37964426).

This gene-disease relationship is also supported by experimental evidence showing that ITPR1 interacts with CA8, an ITPR1-regulating protein implicated in spinocerebellar ataxia. Mice heterozygous for Itpr1 null variants exhibit mild coordination deficits (PMID: 11334652), but do not replicate the ataxia phenotype observed in affected individuals with SCA29 missense variants (PMIDs: 8538767).

In summary, there is definitive evidence supporting the relationship between ITPR1 and autosomal dominant spinocerebellar ataxia type 29. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2021 and classified as Definitive. It was reevaluated on January 23, 2025 (SOP Version 11). Although additional evidence was curated, the classification did not change.

ITPR1 encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3) and is enriched in the brain, particularly in the Purkinje cells of the cerebellum. ITPR1 was first reported in relation to autosomal dominant spinocerebellar ataxia type 29 (SCA29) in 2012 (Huang et al., PMID: 22986007). Clinical features include cerebellar ataxia with onset in infancy or childhood, hypotonia, gross motor delay, oculomotor abnormalities, dysarthria, mild-to-moderate intellectual disability or learning disability, and cerebellar atrophy/hypoplasia. ITPR1 has also been reported in relation to autosomal dominant spinocerebellar ataxia type 15 (SCA15), an adult-onset, slowly progressive cerebellar ataxia. Heterozygous missense variants cause SCA29, while heterozygous loss-of-function variants, mainly deletions, cause SCA15. Based on the ClinGen Lumping and Splitting guidance, there are differences in molecular mechanism and phenotype and therefore, the two types of spinocerebellar ataxia were assessed separately. This curation concerns autosomal dominant SCA29. The relationship between ITPR1 and SCA15 will be curated separately by another gene curation expert panel.

This curation includes 9 missense variants that have been reported in 10 probands in 6 publications (PMIDs: 25794864, 27062503, 28620721, 29925855, 31632679), and segregation data in one large family (PMID: 22986007). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The variants are often de novo but may also be inherited from an affected parent, and many are recurrent. Most reported variants cluster in the N-terminal IP3 binding domain, the C-terminal channel domain and the CAR8-binding region (PMID: 37964426). SCA29 variants within or near the IP3-binding domain of IP3R1 (including hotspot variants p.Thr267Met and p.Arg269Trp) abolish IP3-induced Ca2+ channel activity and several also reduce IP3 binding, suggesting that the mechanism of pathogenicity is dominant-negative loss of function (PMID: 30429331). However, the SCA29 variant p.Arg36Cys, located in the suppressor domain, and two variants in the CAR8-binding region (p.Ser1502Asp and p.Val1562Met), exhibit increased IP3 binding and elevation of intracellular Ca2+ signal compared to wild-type ITPR1 (PMIDs: 28620721, 30429331), indicating that both gain and loss of function can lead to SCA29.

Of note, autosomal dominant and recessive forms of Gillespie syndrome, characterized by aniridia, cerebellar ataxia and intellectual disability, have been reported in relation to heterozygous missense variants in the C-terminal domain of ITPR1 or biallelic truncating variants, respectively. The relationship between ITPR1 and Gillespie syndrome was evaluated separately. No obvious genotype-phenotype correlations have been observed for the SCA29 and Gillespie syndrome variants clustered in the C-terminal domain (PMID: 37964426).

This gene-disease relationship is supported by experimental evidence showing that ITPR1 interacts with CA8, an ITPR1-regulating protein implicated in spinocerebellar ataxia. Mice heterozygous for Itpr1 null variants exhibit mild coordination deficits (PMID: 11334652), but to dot replicate the ataxia phenotype observed in affected individuals with SCA29 missense variants (PMIDs: 8538767).

In summary, there is definitive evidence supporting the relationship between ITPR1 and autosomal dominant spinocerebellar ataxia type 29. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2021 and classified as Definitive. It was reevaluated on January 23, 2025 (SOP Version 11). Although additional evidence was curated, the classification did not change.