VCV002637458.2 - ClinVar

NM_001378452.1(ITPR1):c.6337G>A (p.Asp2113Asn)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378452.1(ITPR1):c.6337G>A (p.Asp2113Asn)

Variation ID: 2637458 Accession: VCV002637458.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p26.1 3: 4779595 (GRCh38) [ NCBI UCSC ] 3: 4821279 (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	Nov 20, 2023	Feb 20, 2024	Dec 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378452.1:c.6337G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365381.1:p.Asp2113Asn	missense
NM_001099952.4:c.6193G>A	NP_001093422.2:p.Asp2065Asn	missense
NM_001168272.2:c.6292G>A	NP_001161744.1:p.Asp2098Asn	missense
NM_002222.7:c.6148G>A	NP_002213.5:p.Asp2050Asn	missense
NC_000003.12:g.4779595G>A
NC_000003.11:g.4821279G>A
NG_016144.1:g.291248G>A
NG_016144.2:g.291249G>A

... more HGVS ... less HGVS

Protein change

D2050N, D2065N, D2098N, D2113N

Other names

Canonical SPDI

NC_000003.12:4779594:G:A

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	1708	1912

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Oct 25, 2023	RCV003404756.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 9, 2023	RCV003669418.2

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 (Oct 25, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004122130.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: Variant summary: ITPR1 c.6148G>A (p.Asp2050Asn) results in a conservative amino acid change located in the RyR/IP3R homology associated domain (IPR013662) of the encoded protein sequence. … (more) Variant summary: ITPR1 c.6148G>A (p.Asp2050Asn) results in a conservative amino acid change located in the RyR/IP3R homology associated domain (IPR013662) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249134 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6148G>A in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Dec 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004392477.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2050 of the ITPR1 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2050 of the ITPR1 protein (p.Asp2050Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITPR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

Variant summary: ITPR1 c.6148G>A (p.Asp2050Asn) results in a conservative amino acid change located in the RyR/IP3R homology associated domain (IPR013662) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249134 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6148G>A in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2050 of the ITPR1 protein (p.Asp2050Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITPR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001378452.1(ITPR1):c.6337G>A (p.Asp2113Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...