Submissions for variant NM_001378452.1(ITPR1):c.4684G>A (p.Val1562Met)

dbSNP: rs397514535

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624908	SCV000741833	pathogenic	Inborn genetic diseases	2017-01-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091682	SCV001247863	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001091682	SCV001447438	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV003389037	SCV004101254	pathogenic	Neurodevelopmental disorder	2023-05-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032771	SCV005398235	pathogenic	Spinocerebellar ataxia type 29	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and observed in individuals with ITPR1-related features (DECIPHER, PMID: 26770814). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been reported to segregate with spinocerebellar ataxia in many affected individuals from this individual's family, and another unrelated family (PMIDs: 26770814, 22986007). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001091682	SCV005874581	pathogenic	not provided	2024-08-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: abolished interaction with carbonic anhydrase-related protein VIII (CA8) and CA8-mediated inhibition of ITPR1 (PMID: 30429331); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11445634, 28659154, 23495097, 14981189, 31730387, 32290556, 26770814, 25794864, 28620721, 27062503, 37964426, 38860480, 30429331, 22986007)
OMIM	RCV000032771	SCV000056535	pathogenic	Spinocerebellar ataxia type 29	2004-12-28	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001091682	SCV001743050	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091682	SCV001951167	pathogenic	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV004767027	SCV005091237	likely pathogenic	Spinocerebellar ataxia type 15/16	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team