VCV001802278.7 - ClinVar

NM_001378452.1(ITPR1):c.1813C>G (p.Leu605Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378452.1(ITPR1):c.1813C>G (p.Leu605Val)

Variation ID: 1802278 Accession: VCV001802278.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p26.1 3: 4667476 (GRCh38) [ NCBI UCSC ] 3: 4709160 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 11, 2022	Aug 11, 2024	May 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378452.1:c.1813C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365381.1:p.Leu605Val	missense
NM_001099952.4:c.1813C>G	NP_001093422.2:p.Leu605Val	missense
NM_001168272.2:c.1768C>G	NP_001161744.1:p.Leu590Val	missense
NM_002222.5:c.1768C>G
NM_002222.7:c.1768C>G	NP_002213.5:p.Leu590Val	missense
NC_000003.12:g.4667476C>G
NC_000003.11:g.4709160C>G
NG_016144.2:g.179130C>G

... more HGVS ... less HGVS

Protein change

L590V, L605V

Other names

Canonical SPDI

NC_000003.12:4667475:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ITPR1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1712	1916

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Spinocerebellar ataxia type 29	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 23, 2024	RCV002465091.4
ITPR1-related syndromic and non-syndromic hereditary ataxias	Uncertain significance (1)	criteria provided, single submitter	Apr 13, 2022	RCV002466761.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 29 Affected status: yes Allele origin: unknown	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology Accession: SCV002759487.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: The c.1813C>G variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. … (more) The c.1813C>G variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. The variant was neither published nor reported to clinical databases like ClinVar, Human Genome Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen2, MutationTaster2, CADD etc predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. (less) Number of individuals with the variant: 1 Secondary finding: no Method: exome sequencing
Uncertain significance (Apr 13, 2022)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	ITPR1-related syndromic and non-syndromic hereditary ataxias Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002762701.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Publications: PubMed (2) PubMed: 27062503‚ 27108798 Comment: The ITPR1 c.1768C>G (p.Leu590Val) missense variant results in the substitution of leucine at amino acid position 590 with valine. To our knowledge, this variant has … (more) The ITPR1 c.1768C>G (p.Leu590Val) missense variant results in the substitution of leucine at amino acid position 590 with valine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The c.1768C>G variant lies within the IP3-binding domain, which is reported to function in protein binding (Barresi et al. 2016; McEntagart et al. 2016). Another variant at the same position (p.Leu590LPhe) is reported as likely pathogenic in ClinVar. Missense variants are a common mechanism of ITPR1-related syndromic and non-syndromic hereditary ataxias (Barresi et al. 2016). Based on the available evidence, the c.1768C>G (p.Leu590Val) variant is classified as a variant of uncertain significance for ITPR1-related syndromic and non-syndromic hereditary ataxias. (less)
Likely pathogenic (May 23, 2024)	criteria provided, single submitter (ACGS Guidelines, 2020) Method: clinical testing	Spinocerebellar ataxia type 29 Affected status: yes Allele origin: unknown	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues Accession: SCV005094589.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024

Comment:

The c.1813C>G variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. The variant was neither published nor reported to clinical databases like ClinVar, Human Genome Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen2, MutationTaster2, CADD etc predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies.

Comment:

The ITPR1 c.1768C>G (p.Leu590Val) missense variant results in the substitution of leucine at amino acid position 590 with valine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The c.1768C>G variant lies within the IP3-binding domain, which is reported to function in protein binding (Barresi et al. 2016; McEntagart et al. 2016). Another variant at the same position (p.Leu590LPhe) is reported as likely pathogenic in ClinVar. Missense variants are a common mechanism of ITPR1-related syndromic and non-syndromic hereditary ataxias (Barresi et al. 2016). Based on the available evidence, the c.1768C>G (p.Leu590Val) variant is classified as a variant of uncertain significance for ITPR1-related syndromic and non-syndromic hereditary ataxias.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia.	Barresi S	Clinical genetics	2017	PMID: 27062503
A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.	McEntagart M	American journal of human genetics	2016	PMID: 27108798

Text-mined citations for this variant ...

Record last updated Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_001378452.1(ITPR1):c.1813C>G (p.Leu605Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...