ClinVar Miner

Submissions for variant NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp) (rs886039392)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254736 SCV000321785 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing The R269W variant in the ITPR1 gene has been reported previously as a de novo variant in individuals with ITPR1-related disorder and as being inherited in a family with ITPR1-related disorder (Fitzgerald et al., 2015; Barresi et al., 2017; Zambonin et al., 2017). The R269W variant is not observed in large population cohorts (Lek et al., 2016). The R269W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R269W as a pathogenic variant.
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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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; Gillespie syndrome 2017-12-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute 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
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.
Institute of Human Genetics, Klinikum rechts der Isar RCV000995787 SCV001150135 pathogenic Gillespie syndrome 2018-01-22 no assertion criteria provided clinical testing

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