ClinVar Miner

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

dbSNP: rs886039392
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Total submissions: 18
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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
Labcorp Genetics (formerly Invitae), Labcorp 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.
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 Centre For Genomic Medicine, NCGM 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000677359 SCV005398111 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 congenital non progressive spinocerebellar ataxia 29 (SCA29) (MIM#117360). Missense variants have been reported to cause both loss and gain of function mechanisms (PMID: 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. There is no established genotype-phenotype correlation regarding the location of a variant and its mode of inheritance, however only biallelic truncating variants have been reported for recessive disease (PMID: 29925855). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes. (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MIR domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Arg269Gly) has been reported in a single de novo patient with SCA29 (PMID: 28659154) and p.(Arg269Leu) has been classified as pathogenic by a clinical laboratory in ClinVar. ClinVar also contains a VUS entry for p.(Arg269Gln). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurring de novo mutation that has been reported many times as pathogenic in patients with SCA29 (ClinVar, DECIPHER, PMID: 28659154, PMID:29925855). (SP) 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
Suma Genomics RCV000850563 SCV002097011 uncertain significance Spinocerebellar ataxia type 29; Spinocerebellar ataxia type 15/16; Gillespie syndrome flagged submission clinical testing
Solve-RD Consortium RCV003335291 SCV005091239 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

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