Submissions for variant NM_001378452.1(ITPR1):c.2299C>T (p.Arg767Cys)

gnomAD frequency: 0.00011  dbSNP: rs377248442

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001146935	SCV001307700	likely benign	Autosomal dominant cerebellar ataxia	2018-01-13	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.
Athena Diagnostics	RCV001288215	SCV001475174	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
GeneDx	RCV001288215	SCV001992456	uncertain significance	not provided	2020-12-14	criteria provided, single submitter	clinical testing	Maternally inherited in one individual with autism identified through sequencing (Guo et al., 2018); 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: 30564305)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288215	SCV004271189	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 752 of the ITPR1 protein (p.Arg752Cys). This variant is present in population databases (rs377248442, gnomAD 0.02%). ClinVar contains an entry for this variant (Variation ID: 901202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITPR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587050	SCV005077470	uncertain significance	not specified	2024-04-29	criteria provided, single submitter	clinical testing	Variant summary: ITPR1 c.2254C>T (p.Arg752Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249100 control chromosomes. c.2254C>T has been reported in the literature in one individual affected with Autism, withou strong evidence for causality (Guo_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Spinocerebellar Ataxia 29. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30564305). ClinVar contains an entry for this variant (Variation ID: 901202). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001288215	SCV005092986	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ITPR1: PP3