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).
ClinVar Genomic variation as it relates to human health
NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(17)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
17
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp)
Variation ID: 265201 Accession: VCV000265201.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p26.1 3: 4645678 (GRCh38) [ NCBI UCSC ] 3: 4687362 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2016 Oct 26, 2024 May 25, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001378452.1:c.805C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365381.1:p.Arg269Trp missense NM_001099952.4:c.805C>T NP_001093422.2:p.Arg269Trp missense NM_001168272.2:c.805C>T NP_001161744.1:p.Arg269Trp missense NM_002222.7:c.805C>T NP_002213.5:p.Arg269Trp missense NC_000003.12:g.4645678C>T NC_000003.11:g.4687362C>T NG_016144.1:g.157331C>T - Protein change
- R269W
- Other names
- -
- Canonical SPDI
- NC_000003.12:4645677:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ITPR1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1712 | 1916 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2022 | RCV000254736.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2016 | RCV000623132.3 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2021 | RCV000677359.10 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Dec 31, 2017 | RCV000850563.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2018 | RCV000995787.6 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV003335291.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2022 | RCV002278250.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 09, 2018)
|
criteria provided, single submitter
Method: research
|
Spinocerebellar ataxia type 29
Affected status: yes
Allele origin:
de novo
|
Schule lab, Hertie Institute for Clinical Brain Research
Accession: SCV000700181.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018
Comment:
reduced fractional Ca2+ release upon induction by IP3
|
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Germany
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: unspecified
Geographic origin: United States
|
|
|
Likely pathogenic
(Jul 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000855644.1
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely pathogenic
(Dec 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Gillespie syndrome
Spinocerebellar ataxia type 15/16 Spinocerebellar ataxia type 29
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992778.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
|
|
|
Pathogenic
(Jan 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Gillespie syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150135.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Spinocerebellar ataxia type 29
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164396.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446789.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Strabismus (present) , Cerebellar ataxia (present) , Tremor (present) , Scoliosis (present) , Depletion of mitochondrial DNA in muscle tissue (present) , Mitochondrial respiratory chain … (more)
Strabismus (present) , Cerebellar ataxia (present) , Tremor (present) , Scoliosis (present) , Depletion of mitochondrial DNA in muscle tissue (present) , Mitochondrial respiratory chain defects (present) (less)
Sex: male
|
|
|
Pathogenic
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Spinocerebellar ataxia type 29
Affected status: yes
Allele origin:
de novo
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519143.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 29
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012332.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Overgrowth (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Delayed speech and language development (present) , Cerebellar atrophy (present) … (more)
Overgrowth (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Delayed speech and language development (present) , Cerebellar atrophy (present) , Specific learning disability (present) , Macrotia (present) , Cerebellar ataxia (present) , Macrocephaly (present) , Intellectual disability (present) (less)
|
|
|
Pathogenic
(Jul 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064357.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(May 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV002564517.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741338.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Generalized hypotonia (present) , Global developmental delay (present) , Visual impairment (present) , Hypospadias, penile (present) , Exotropia (present) , Nystagmus (present) , Amblyopia (present) … (more)
Generalized hypotonia (present) , Global developmental delay (present) , Visual impairment (present) , Hypospadias, penile (present) , Exotropia (present) , Nystagmus (present) , Amblyopia (present) , Hypertelorism (present) , Prominent nasal bridge (present) , Plagiocephaly (present) , Prominent forehead (present) , Wide intermamillary distance (present) (less)
Sex: male
Ethnicity/Population group: Hispanic/El Salvadorian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dystonia (present) , Carious teeth (present) , Allergic conjunctivitis (present) , Titubation (present) , Bilateral ptosis (present) , Obstructive sleep apnea syndrome (present) , Curly … (more)
Dystonia (present) , Carious teeth (present) , Allergic conjunctivitis (present) , Titubation (present) , Bilateral ptosis (present) , Obstructive sleep apnea syndrome (present) , Curly eyelashes (present) , Cerebral palsy (present) , Sleep apnea (present) , Recurrent otitis media (present) , Hypermetropia (present) , Nystagmus (present) , Global developmental delay (present) , Muscular hypotonia (present) , Downslanted palpebral fissures (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321785.10
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
SPINOCEREBELLAR ATAXIA 15
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046252.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
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, … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 29
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048120.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Lipodystrophy (present) , Movement disorder (present)
|
|
|
Pathogenic
(Mar 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001587678.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Spinocerebellar ataxia type 15/16
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091239.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
|
|
Uncertain significance
(-)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Gillespie syndrome
Spinocerebellar ataxia type 15/16 Spinocerebellar ataxia type 29 (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics, Suma Genomics
Accession: SCV002097011.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
Variant confirmed as disease-causing by referring clinical team
Germline Functional Evidence
| Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Schule lab, Hertie Institute for Clinical Brain Research
Accession: SCV000700181.1
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Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. | Synofzik M | European journal of human genetics : EJHG | 2018 | PMID: 29925855 |
| Missense mutation in the ITPR1 gene presenting with ataxic cerebral palsy: Description of an affected family and literature review. | Das J | Neurologia i neurochirurgia polska | 2017 | PMID: 28826917 |
| Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia. | Zambonin JL | Orphanet journal of rare diseases | 2017 | PMID: 28659154 |
| Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. | Barresi S | Clinical genetics | 2017 | PMID: 27062503 |
| Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. | Sasaki M | Journal of neurology | 2015 | PMID: 25794864 |
| Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. | Ohba C | Neurogenetics | 2013 | PMID: 24091540 |
| Novel repeats in ryanodine and IP3 receptors and protein O-mannosyltransferases. | Ponting CP | Trends in biochemical sciences | 2000 | PMID: 10664581 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ITPR1 | - | - | - | - |
Text-mined citations for rs886039392 ...
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Record last updated Oct 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.