3-4645673-C-T

Position:

• chr3-4645673-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.800C>T​(p.Thr267Met) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T267A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4645672-A-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 3-4645673-C-T is Pathogenic according to our data. Variant chr3-4645673-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.800C>T	p.Thr267Met	missense_variant	10/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.800C>T	p.Thr267Met	missense_variant	10/61		NP_001161744.1
ITPR1	NM_001099952.4	c.800C>T	p.Thr267Met	missense_variant	10/59		NP_001093422.2
ITPR1	NM_002222.7	c.800C>T	p.Thr267Met	missense_variant	10/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.800C>T	p.Thr267Met	missense_variant	10/62		NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:6 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory de novo in a 12-year-old female with cerebellar ataxia with tremor (onset in first year of life), significant motor delays, moderate speech delays, hypoplastic cerebellar vermis -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Medicine, Institute for Basic Research in Developmental Disabilities	-	The variant is classified as “Pathogenic” as per the American College of Medical Genetics (ACMG) guidelines (Richards et al. 2015). Two “Strong” criteria (PS1, PS3) are met as the variant has been previously reported to be pathogenic and there is functional evidence to support a damaging effect on intracellular calcium modulation (Ngo et al. 2019; Ohba et al. 2013; Sasaki et al. 2015; Synofzik et al. 2018; Zambonin et al. 2017; Iwama et al. 2019; Kashimada et al. 2019; Won et al. 2020; Gauquelin et al. 2020; Martínez-Rubio et al. 2022; Romaniello et al. 2022; Zhi et al. 2023). Additionally, the variant meets “Moderate” criteria PM2, given that the variant is not present in GnomAD (Chen et al. 2022). “Supporting” criteria PP3 is also met. The Phred-scaled Combined Annotation Dependent Depletion (CADD) score was calculated to be greater 26.2, which suggests that the pathogenicity of the variant is in the 99.8 percentile (Rentzsch et al. 2019). The Sorting Intolerant From Tolerant (SIFT) and PolyPhen scores also support the variant’s pathogenicity and were calculated to be 0 and 0.994 respectively (Ng and Henikoff 2003; Adzhubei, Jordan, and Sunyaev 2013). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Rehabilitation Medicine, Chungnam National University Hospital	Sep 26, 2022	Mutations in the c.800C>T (p.Thr267Met) locus have been documented in the literature for associations with the diagnosis of spinocerebellar ataxia 29. Threonine at position 267 is located at the IRBIT binding region and IP3 binding domain. Variants in the ITPR1 gene have caused loss of function of the IP3R1 protein, thus disrupting calcium release from the endoplasmic reticulum of cells, especially Purkinje cells of the cerebellum, thus causing cerebellar degeneration and characteristics of SCA29. -
Pathogenic, criteria provided, single submitter	research	Schule lab, Hertie Institute for Clinical Brain Research	Feb 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 23, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP3 supporting -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 06, 2021	PS2, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 14, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 267 of the ITPR1 protein (p.Thr267Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 24091540, 31632679). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITPR1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2022	Published functional studies suggest ITPR1 loss-of-function (Synofzik et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31632679, 25794864, 24091540, 29925855, 29878067, 28659154, 30842224, 32290556, 30301590, 32695065, 33163565, 27535533) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2013

- -

Spinocerebellar ataxia type 15/16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.87
MutPred		0.67		Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);Loss of phosphorylation at T267 (P = 0.0523);
MVP		0.92
MPC		1.8
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.73
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044955; hg19: chr3-4687357; COSMIC: COSV56989747;