3-4645678-C-T

Position:

• chr3-4645678-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.805C>T​(p.Arg269Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely 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:17 U:1
• Conservation: PhyloP100: 2.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.824
• PP5: Variant 3-4645678-C-T is Pathogenic according to our data. Variant chr3-4645678-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4645678-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.805C>T	p.Arg269Trp	missense_variant	10/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.805C>T	p.Arg269Trp	missense_variant	10/61		NP_001161744.1
ITPR1	NM_001099952.4	c.805C>T	p.Arg269Trp	missense_variant	10/59		NP_001093422.2
ITPR1	NM_002222.7	c.805C>T	p.Arg269Trp	missense_variant	10/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.805C>T	p.Arg269Trp	missense_variant	10/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.805C>T	p.Arg269Trp	missense_variant	10/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.805C>T	p.Arg269Trp	missense_variant	10/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.805C>T	p.Arg269Trp	missense_variant	10/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.805C>T	p.Arg269Trp	missense_variant	10/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.805C>T	p.Arg269Trp	missense_variant	8/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.805C>T	p.Arg269Trp	missense_variant	10/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.805C>T	p.Arg269Trp	missense_variant	10/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	research	Schule lab, Hertie Institute for Clinical Brain Research	Feb 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with congenital non progressive spinocerebellar ataxia 29 (SCA29) (MIM#117360). Missense variants have been reported to cause both loss and gain of function mechanisms (PMID: 28620721; 29925855; OMIM), while variants resulting in a truncated protein have been reported to cause loss of function only (PMID: 29925855). (I) 0108 - This gene is associated with both recessive and dominant disease. There is no established genotype-phenotype correlation regarding the location of a variant and its mode of inheritance, however only biallelic truncating variants have been reported for recessive disease (PMID: 29925855). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes. (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MIR domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Arg269Gly) has been reported in a single de novo patient with SCA29 (PMID: 28659154) and p.(Arg269Leu) has been classified as pathogenic by a clinical laboratory in ClinVar. ClinVar also contains a VUS entry for p.(Arg269Gln). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurring de novo mutation that has been reported many times as pathogenic in patients with SCA29 (ClinVar, DECIPHER, PMID: 28659154, PMID:29925855). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 23, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 13, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2017	- -

Spinocerebellar ataxia type 15/16 Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -

Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Uncertain significance, flagged submission	clinical testing	Suma Genomics	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2016

- -

Gillespie syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jan 22, 2018

- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

May 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.72
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		0.94
MutPred		0.56		Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.82
gMVP		0.83

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: rs886039392; hg19: chr3-4687362; COSMIC: COSV57006244;