chr3-4815176-CAGA-C

Position:

• chr3-4815176-CAGA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.7831_7833del​(p.Lys2611del) variant causes a 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 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.25

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 235919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4815176-CAGA-C is described in Lovd as [Likely_pathogenic]. Variant chr3-4815176-CAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7831_7833del	p.Lys2611del	inframe_deletion	59/62	ENST00000649015.2	NP_001365381.1
LOC124906209	XR_007095795.1	n.725-748_725-746del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7831_7833del	p.Lys2611del	inframe_deletion	59/62		NM_001378452.1	ENSP00000497605
	ENST00000693140.1	n.581+10567_581+10569del		intron_variant, non_coding_transcript_variant

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gillespie syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Jul 09, 2024	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. -
Pathogenic, criteria provided, single submitter	research	Schule lab, Hertie Institute for Clinical Brain Research	Feb 09, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2022	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). 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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs878853175; hg19: chr3-4856860;