NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met) AND Spinocerebellar ataxia type 29

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: May 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000677366.13

Allele description [Variation Report for NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)]

NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)

Gene:

ITPR1:inositol 1,4,5-trisphosphate receptor type 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p26.1

Genomic location:

Preferred name:

NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)

Other names:

p.Thr267Met

HGVS:

NC_000003.12:g.4645673C>T
NG_016144.1:g.157326C>T
NM_001099952.4:c.800C>T
NM_001168272.2:c.800C>T
NM_001378452.1:c.800C>TMANE SELECT
NM_002222.7:c.800C>T
NP_001093422.2:p.Thr267Met
NP_001161744.1:p.Thr267Met
NP_001365381.1:p.Thr267Met
NP_002213.5:p.Thr267Met
NC_000003.11:g.4687357C>T
NM_002222.5:c.800C>T
NM_002222.6:c.800C>T
NM_002222.7:c.800C>T

Protein change:

T267M

Links:

dbSNP: rs797044955

NCBI 1000 Genomes Browser:

rs797044955

Molecular consequence:

NM_001099952.4:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001168272.2:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378452.1:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002222.7:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Name:: Spinocerebellar ataxia type 29 (SCA29)
Synonyms:: Cerebellar ataxia early-onset nonprogressive; CEREBELLAR ATAXIA, CONGENITAL NONPROGRESSIVE, AUTOSOMAL DOMINANT; Spinocerebellar ataxia 29, congenital nonprogressive
Identifiers:: MONDO: MONDO:0007298; MedGen: C1861732; Orphanet: 208513; OMIM: 117360

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700188	Schule lab, Hertie Institute for Clinical Brain Research	criteria provided, single submitter (Synofzik et al. (Eur J Hum Genet. 2018))	Pathogenic (Feb 9, 2018)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV002512364	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581407	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003929451	Genome Medicine, Institute for Basic Research in Developmental Disabilities	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 23315928, 33163565, 30842224, 30301590, 36233161, 12824425, 31632679, 24091540, 30371827, 35743164, 25794864, 29925855, 32695065, 28659154, 36585006, 25741868
SCV004032470	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004036077	Department of Rehabilitation Medicine, Chungnam National University Hospital	no assertion criteria provided	Pathogenic (Sep 26, 2022)	de novo	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25794864, 29925855, 28659154, 31632679

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
Korean	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
Middle Eastern	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
unspecified	de novo	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

Predicting functional effect of human missense mutations using PolyPhen-2.

Adzhubei I, Jordan DM, Sunyaev SR.

Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20. doi: 10.1002/0471142905.hg0720s76.

PubMed [citation]

PMID:: 23315928
PMCID:: PMC4480630

See all PubMed Citations (17)

Details of each submission

From Schule lab, Hertie Institute for Clinical Brain Research, SCV000700188.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	unspecified	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV000807309.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (2)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512364.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581407.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genome Medicine, Institute for Basic Research in Developmental Disabilities, SCV003929451.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Middle Eastern	not provided	not provided	not provided	clinical testing	PubMed (16)
2	Middle Eastern	not provided	not provided	not provided	clinical testing	PubMed (16)
3	Middle Eastern	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV004032470.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Rehabilitation Medicine, Chungnam National University Hospital, SCV004036077.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Korean	1	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000807309	Baylor Genetics	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2017)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000807309

Baylor Genetics

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 1, 2017)

de novo

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Last Updated: Jan 13, 2025

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