VCV000585154.5 - ClinVar

NM_001378452.1(ITPR1):c.4333G>A (p.Val1445Met)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic

2 out of 3 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378452.1(ITPR1):c.4333G>A (p.Val1445Met)

Variation ID: 585154 Accession: VCV000585154.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p26.1 3: 4697198 (GRCh38) [ NCBI UCSC ] 3: 4738882 (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 14, 2018	Apr 13, 2025	Feb 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378452.1:c.4333G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365381.1:p.Val1445Met	missense
NM_001099952.4:c.4306G>A	NP_001093422.2:p.Val1436Met	missense
NM_001168272.1:c.4288G>A
NM_001168272.2:c.4288G>A	NP_001161744.1:p.Val1430Met	missense
NM_002222.7:c.4261G>A	NP_002213.5:p.Val1421Met	missense
NC_000003.12:g.4697198G>A
NC_000003.11:g.4738882G>A
NG_016144.1:g.208851G>A

... more HGVS ... less HGVS

Protein change

V1421M, V1430M, V1436M, V1445M

Other names

Canonical SPDI

NC_000003.12:4697197:G:A

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA351632360 dbSNP: rs1559718601 VarSome

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
Gene	OMIM	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	2117	2423

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.
Gillespie syndrome Spinocerebellar ataxia type 15/16 Spinocerebellar ataxia type 29	not provided (1)	no classification provided	-	RCV002311994.9
ITPR1-related disorders	Likely pathogenic (1)	criteria provided, single submitter	Feb 15, 2024	RCV005250102.1
Spinocerebellar ataxia type 29	Likely pathogenic (1)	criteria provided, single submitter	Jul 26, 2022	RCV002268270.9

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Jul 26, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Spinocerebellar ataxia type 29 (Sporadic)	Institute of Human Genetics, University of Goettingen Accession: SCV002550877.2 First in ClinVar: Jul 29, 2022 Last updated: Apr 13, 2025	Comment: show The variant c.4261G>A (p.(Val1421Met)) in exon 33 of the ITPR1-gene is not found in the gnomAD database, it affects a highly conserved nucleotide, a highly conserved amino acid and there is a small physicochemical difference between Val and Met. This variant has a pathogenic computational verdict based on in silico predictions algorithms. It was found to be de novo in our patient. ACMG criteria used for classification: PM2, PM6, PP2, BP4. (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Clinical Features: Motor delay (present) , Gait ataxia (present) , Expressive language delay (present) , Poor fine motor coordination (present) Zygosity: 1 Single Heterozygote Sex: female Platform type: Next-generation exome sequencing Platform name: NextSeq

Likely pathogenic (Feb 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	ITPR1-related disorders	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV005900715.1 First in ClinVar: Mar 29, 2025 Last updated: Mar 29, 2025	Comment: show The ITPR1 gene is highly constrained (Z-score= 6.2 and pLI = 1), which suggests it is intolerant to variation. The c.4288G>A (p.Val1430Met) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has not been previously reported or functionally characterized in the literature to our knowledge. The c.4288G>A (p.Val1430Met) variant is absent from the gnomAD population database and thus is presumed to be rare. 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, c.4288G>A (p.Val1430Met) is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	Gillespie syndrome Spinocerebellar ataxia type 15/16 Spinocerebellar ataxia type 29	GenomeConnect, ClinGen Accession: SCV000840339.2 First in ClinVar: Oct 14, 2018 Last updated: Apr 13, 2025	Comment: show GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation: 1 Collection method: phenotyping only Allele origin: de novo Affected status: unknown more Observation 1 Collection method: phenotyping only Allele origin: de novo Affected status: unknown Clinical Features: Myopia (present) , Abnormality of eye movement (present) , Memory impairment (present) , Generalized hypotonia (present) , EEG abnormality (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Cerebral palsy (present) , Morphological abnormality of the central nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Feeding difficulties (present) Indication for testing: Diagnostic Test name: Gene Panel Sequencing Age: 20-29 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2017-11-07 Testing laboratory interpretation: Uncertain significance

Comment:

The variant c.4261G>A (p.(Val1421Met)) in exon 33 of the ITPR1-gene is not found in the gnomAD database, it affects a highly conserved nucleotide, a highly conserved amino acid and there is a small physicochemical difference between Val and Met. This variant has a pathogenic computational verdict based on in silico predictions algorithms. It was found to be de novo in our patient. ACMG criteria used for classification: PM2, PM6, PP2, BP4.

Comment:

The ITPR1 gene is highly constrained (Z-score= 6.2 and pLI = 1), which suggests it is intolerant to variation. The c.4288G>A (p.Val1430Met) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has not been previously reported or functionally characterized in the literature to our knowledge. The c.4288G>A (p.Val1430Met) variant is absent from the gnomAD population database and thus is presumed to be rare. 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, c.4288G>A (p.Val1430Met) is classified as Likely Pathogenic.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1559718601 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025