3-4815144-T-C

Variant names:

• chr3-4815144-T-C
• rs1553758021
• NM_001378452.1:c.7793T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.7793T>C​(p.Ile2598Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2598N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.95
• Publications: 3 publications found

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001378452.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4815144-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 522562.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 3-4815144-T-C is Pathogenic according to our data. Variant chr3-4815144-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.7793T>C	p.Ile2598Thr	missense	Exon 59 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.7748T>C	p.Ile2583Thr	missense	Exon 58 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.7649T>C	p.Ile2550Thr	missense	Exon 56 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.7793T>C	p.Ile2598Thr	missense	Exon 59 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.7769T>C	p.Ile2590Thr	missense	Exon 59 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.7766T>C	p.Ile2589Thr	missense	Exon 59 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 11, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28659154, 33163565, 29997391, 34445196, 35599849)

Jun 11, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene. Computational tools predict that this variant is damaging.

Apr 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spinocerebellar ataxia type 29 Pathogenic:2

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 25, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.90 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000559630 /PMID: 28659154 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33163565). A different missense change at the same codon (p.Ile2598Asn) has been reported to be associated with ITPR1 related disorder (ClinVar ID: VCV000522562 /PMID: 27862915). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

ITPR1-associated cerebellar ataxia spectrum disorder Pathogenic:1

Dec 15, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.52		Loss of stability (P = 0.0105)
MVP		0.95
MPC		2.2
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553758021; hg19: chr3-4856828;