Submissions for variant NM_001378452.1(ITPR1):c.823G>A (p.Ala275Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788461	SCV005397998	likely pathogenic	Spinocerebellar ataxia type 29	2024-09-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with spinocerebellar ataxia 29, congenital nonprogressive (MIM#117360), Gillespie syndrome (MIM#206700), and spinocerebellar ataxia 15 (MIM#606658). Missense variants have been reported to cause both loss and gain of function mechanisms (PMIDs: 28620721, 29925855, OMIM), while variants resulting in a truncated protein have been reported to cause loss of function only (PMID: 29925855). (I) 0108 - This gene is associated with both recessive and dominant disease. Only biallelic truncating variants have been reported for recessive Gillespie syndrome (MIM#206700) (PMID: 29925855), but otherwise there is no clear genotype-phenotype correlation regarding the location of a variant and its associated condition. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been shown in association with de novo ITPR1 ataxia (PMID: 29925855). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. One individual with global developmental delay, nystagmus, microcephaly, hypotonia, renal, ataxia and aplasia/hypoplasia of the cerebellum has been reported (DECIPHER). While the inheritance was unknown, the variant was classified as likely pathogenic. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV004798082	SCV005419727	uncertain significance	not provided	2024-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge