NM_001378452.1:c.7831_7833delAAG

Variant names:

• chr3-4815176-CAGA-C
• rs878853175
• NM_001378452.1:c.7831_7833delAAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.7831_7833delAAG​(p.Lys2611del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.25
• Publications: 12 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001378452.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-4815176-CAGA-C is Pathogenic according to our data. Variant chr3-4815176-CAGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 235919.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.7831_7833delAAG	p.Lys2611del	conservative_inframe_deletion	Exon 59 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.7786_7788delAAG	p.Lys2596del	conservative_inframe_deletion	Exon 58 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.7687_7689delAAG	p.Lys2563del	conservative_inframe_deletion	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.7831_7833delAAG	p.Lys2611del	conservative_inframe_deletion	Exon 59 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.7807_7809delAAG	p.Lys2603del	conservative_inframe_deletion	Exon 59 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.7804_7806delAAG	p.Lys2602del	conservative_inframe_deletion	Exon 59 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gillespie syndrome Pathogenic:4

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Dec 20, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 09, 2024

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant causes a change in protein length as a result of an in-frame deletion of one aminoacid at protein position 2611. A de novo occurrence of this variant in the index patient was confirmed. The variant has furthermore been reported de novo in multiple patients affected with Gillespie Syndrome (PMID: 27108797, 27108798). Experimental studies demonstrated that the variant causes a deleterious effect on protein function by affecting the calcium release channels on ITPR1 structure (PMID: 27108797). The variant is likely to be associated to the disease and has been reported in multiple unrelated individuals affected with Gillespie Syndrome. The variant has been classified in five entries in ClinVar as pathogenic (Clinvar ID: 235919). This variant is classified as very rare since it is absent in gnomAD v4.1.0. In summary, the variant is classified as pathogenic.

Dec 04, 2023

Department of Rehabilitation, Anhui Provincial Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is a deletion mutation, which results in a change in the length of the protein, but does not cause any alteration to the open reading frame.

not provided Pathogenic:2

Aug 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.7642_7644del, results in the deletion of 1 amino acid(s) of the ITPR1 protein (p.Lys2548del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ITPR1 function (PMID: 27108797). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 235919). This variant is also known as c.7687_7689del; p.Lys2596del. This variant has been observed in individual(s) with autosomal dominant Gillespie syndrome (PMID: 27108797, 27108798, 30249237). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

Dec 16, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on calcium release channels (PMID: 27108797); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35118825, 27108798, 25356970, 29925855, 30249237, 28698159, 32637629, 31785789, 27108797)

Inborn genetic diseases Pathogenic:1

May 14, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=38/62	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: rs878853175; hg19: chr3-4856860;