NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 14, 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:: RCV001552791.13

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]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001773550	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 12, 2022)	germline	clinical testing	Citation Link,
SCV002051641	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003525035	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24091540, 31632679, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001773550

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 12, 2022)

germline

clinical testing

Citation Link,

SCV002051641

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 6, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003525035

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood.

Ohba C, Osaka H, Iai M, Yamashita S, Suzuki Y, Aida N, Shimozawa N, Takamura A, Doi H, Tomita-Katsumoto A, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Eto Y, Tanaka F, Matsumoto N, Saitsu H.

Neurogenetics. 2013 Nov;14(3-4):225-32. doi: 10.1007/s10048-013-0375-8. Epub 2013 Oct 4.

PubMed [citation]

PMID:: 24091540

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001773550.3

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

Description

Published functional studies suggest ITPR1 loss-of-function (Synofzik et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31632679, 25794864, 24091540, 29925855, 29878067, 28659154, 30842224, 32290556, 30301590, 32695065, 33163565, 27535533)

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002051641.2

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

Description

PS2, PS3, PS4

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003525035.2

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 267 of the ITPR1 protein (p.Thr267Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 24091540, 31632679). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208786). 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. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jan 13, 2025

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