Submissions for variant NM_001378452.1(ITPR1):c.4421C>T (p.Thr1474Ile)

gnomAD frequency: 0.00048  dbSNP: rs188558398

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000992197	SCV001144268	benign	not provided	2019-02-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147931	SCV001308788	likely benign	Autosomal dominant cerebellar ataxia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262674	SCV001440624	uncertain significance	Spinocerebellar ataxia type 15/16	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992197	SCV003244918	likely benign	not provided	2025-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002549783	SCV003618553	uncertain significance	Inborn genetic diseases	2021-08-14	criteria provided, single submitter	clinical testing	Unlikely to be causative of ITPR1-related spinocerebellar ataxia (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000992197	SCV005093752	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000992197	SCV005326091	uncertain significance	not provided	2023-11-17	criteria provided, single submitter	clinical testing	Identified in a patient with mitochondrial disease with another variant in ITPR1, phase unknown, who is also reported to have a variant in a gene that causes MELAS, which was thought to be a closer phenotypic fit (PMID: 32980267); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32980267)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056723	SCV005725625	uncertain significance	not specified	2024-11-29	criteria provided, single submitter	clinical testing	Variant summary: ITPR1 c.4349C>T (p.Thr1450Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 249244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ITPR1 causing Spinocerebellar Ataxia 29, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4349C>T in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 804937). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251784	SCV001427526	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003943298	SCV004758108	likely benign	ITPR1-related disorder	2022-05-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).