Submissions for variant NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp)

dbSNP: rs886039392

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254736	SCV000321785	pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduction in IP3-induced calcium ion release (Synofzik et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28826917, 29925855, 25533962, 28211945, 28659154, 27062503, 28135719, 28191890, 31632679, 33093175, 31216405, 33258288, 33084218, 32901917, 33619735, 31785789)
Schule lab, Hertie Institute for Clinical Brain Research	RCV000677359	SCV000700181	pathogenic	Spinocerebellar ataxia type 29	2018-02-09	criteria provided, single submitter	research
Ambry Genetics	RCV000623132	SCV000741338	pathogenic	Inborn genetic diseases	2016-03-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000254736	SCV000855644	likely pathogenic	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000850563	SCV000992778	likely pathogenic	Spinocerebellar ataxia type 29; Spinocerebellar ataxia type 15/16; Gillespie syndrome	2017-12-31	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000995787	SCV001150135	pathogenic	Gillespie syndrome	2018-01-22	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000677359	SCV001164396	pathogenic	Spinocerebellar ataxia type 29	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Arg269Trp variant in ITPR1 was identified by our study in one individual with Spinocerebellar Ataxia. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has also been reported pathogenic in ClinVar (Variation ID: 265201). Trio exome analysis reported in the literature showed this variant to be de novo in three additional individuals with Spinocerebellar Ataxia (PMID: 29925855, 28659154). The heterozygous p.Arg269Trp variant in ITPR1 segregated with disease in three affected relatives from one family (PMID: 27062503). In summary, the p.Arg269Trp variant is pathogenic based off of our findings and multiple de novo reports in the literature. ACMG/AMP Criteria applied: PM2, PP3, PS2, PM6_Strong, PP1 (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254736	SCV001446789	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000677359	SCV001519143	pathogenic	Spinocerebellar ataxia type 29	2021-01-04	criteria provided, single submitter	research
Invitae	RCV000254736	SCV001587678	pathogenic	not provided	2018-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 269 of the ITPR1 protein (p.Arg269Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has also been reported to segregate with autosomal dominant nonprogressive congenital ataxia in a family (PMID: 27062503). It has also been reported to be de novo in an individual affected with spinocerebellar ataxia type 29, which is also characterized by congenital nonprogressive ataxia (PMID: 28659154). ClinVar contains an entry for this variant (Variation ID: 265201). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg269Trp) has been determined to be pathogenic (PMID: 28659154). This suggests that the arginine residue is critical for ITPR1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000677359	SCV002012332	pathogenic	Spinocerebellar ataxia type 29	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000265201.12, PMID: 29925855, 28659154, 28826917, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.718, 3Cnet: 0.944, PP3). Patient's phenotype is considered compatible with Spinocerebellar Ataxia 29 (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetic Services Laboratory, University of Chicago	RCV000254736	SCV002064357	pathogenic	not provided	2020-07-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ITPR1 gene demonstrated a sequence change, c.805C>T, in exon 10 that results in an amino acid change, p.Arg269Trp. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg269Trp change has been described in the heterozygous state in a family with non-progressive congenital ataxia (PMID: 27062503) and a family with infantile-onset cerebellar ataxia with delayed motor development and intellectual disability (PMID: 28826917). This sequence change has also been described as a de novo variant in two individuals with early-onset ataxia (PMID: 29925855) and an individual with spinocerebellar ataxia (PMID: 28659154). Functional studies have demonstrated impaired protein function in the presence of this sequence change (PMID: 29925855). The p.Arg269Trp change affects a highly conserved amino acid residue located in a domain of the ITPR1 protein that is known to be functional. The p.Arg269Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, MutationTaster, REVEL). Additionally, a different amino acid change at the same location (p.Arg269Gly) has been reported as pathogenic for autosomal dominant non-progressive cerebellar ataxia (PMID: 27062503). These collective evidences suggest that this is a pathogenic sequence change.
Suma Genomics	RCV000850563	SCV002097011	uncertain significance	Spinocerebellar ataxia type 29; Spinocerebellar ataxia type 15/16; Gillespie syndrome		criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002278250	SCV002564517	pathogenic	Neurodevelopmental disorder	2022-05-25	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335291	SCV004046252	pathogenic	Spinocerebellar ataxia type 15/16		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous de novo (or suspected de novo) variant in numerous individuals with Spinocerebellar Ataxia 15 (PMID: 27062503, 25533962, 28826917, 28191890, 28135719, 28659154, 29925855, 31216405, 33258288). It is absent from the gnomAD population database and thus is presumed to be rare. The c.805C>T (p.Arg269Trp) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.805C>T (p.Arg269Trp) variant is classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000677359	SCV004048120	pathogenic	Spinocerebellar ataxia type 29		criteria provided, single submitter	clinical testing	The missense variant p.R269W in ITPR1 (NM_002222.7) has been previously reported in individuals affected with Spinocerebellar ataxia 29 (Synofzik et al, 2018). Published functional studies demonstrate a reduction in IP3-induced calcium ion release. The p.R269W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between arginine and tryptophan. The p.R269W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 269 of ITPR1 is conserved in all mammalian species. The nucleotide c.805 in ITPR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.