rs1057518026

Variant names:

• chr3-4521038-G-A
• rs1057518026
• NM_001378452.1:c.107G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.107G>A​(p.Arg36His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.52
• Publications: 1 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4521037-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1350168.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 3-4521038-G-A is Pathogenic according to our data. Variant chr3-4521038-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372854.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.107G>A	p.Arg36His	missense_variant	Exon 2 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.107G>A	p.Arg36His	missense_variant	Exon 4 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460882 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111164

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg36 amino acid residue in ITPR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27572814, 28620721). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 36 of the ITPR1 protein (p.Arg36His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372854). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R36H variant in the ITPR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R36H variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R36H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R36H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Spinocerebellar ataxia type 29 Pathogenic:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely 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 nonprogressive spinocerebellar ataxia 29 (SCA29; MIM#117360). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 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 N-terminal suppressor domain (PMID: 30197841). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg36Cys) variant has been reported in a heterozygote state in an individual with SCA29. The variant was inherited from an affected mother who was found to be de novo for the variant. Functional studies showed this variant has a gain of function effect on channel function (PMID: 30197841). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS, however recent reports classify it as likely pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Uncertain:1

Feb 26, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.107G>A (p.R36H) alteration is located in exon 4 (coding exon 2) of the ITPR1 gene. This alteration results from a G to A substitution at nucleotide position 107, causing the arginine (R) at amino acid position 36 to be replaced by a histidine (H). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the ITPR1 c.107G>A alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R36 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.R36 amino acid is located in the N-terminal supressor domain of the IP3 receptor type 1 isoform 2 protein. This domain functions in attenuating the affinity of the IP3-binding core domain to a physiological range, and is also a binding target for many proteins that modulate the channel activity of the receptor. The domain contains a head subdomain forming a beta-trefoil fold. The R36 residue is located on the molecular surface of the head subdomain and could potentially interact simultaneously with the core domain; indeed it was found that mutating this residue to R36E significantly increased IP3 binding affinity (Bosanac, 2002b). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.R36H alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;M;.;.;.;M;M;M
PhyloP100		9.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.4	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.;D;D;.;T;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.62
MutPred		0.62		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.92
MPC		2.0
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.69
Mutation Taster		=67/33	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: rs1057518026; hg19: chr3-4562722;