ClinVar Genomic variation as it relates to human health
NM_032790.4(ORAI1):c.100A>C (p.Ser34Arg)
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.
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(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032790.4(ORAI1):c.100A>C (p.Ser34Arg)
Variation ID: 541941 Accession: VCV000541941.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 122064747 (GRCh37) [ NCBI UCSC ] 12: 121626842 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 10, 2018 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032790.4:c.100A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_116179.2:p.Ser34Arg NC_000012.12:g.121626842A>C NC_000012.11:g.122064747A>C NG_007500.1:g.5273A>C NG_187556.1:g.533A>C LRG_93:g.5273A>C LRG_93t1:c.100A>C LRG_93p1:p.Ser34Arg - Protein change
- S34R
- Other names
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- Canonical SPDI
- NC_000012.12:121626841:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00052
Trans-Omics for Precision Medicine (TOPMed) 0.00072
Exome Aggregation Consortium (ExAC) 0.00081
The Genome Aggregation Database (gnomAD) 0.00102
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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LOC130008987 | - | - | - |
GRCh38 GRCh38 |
- | 190 |
ORAI1 | - | - |
GRCh38 GRCh38 GRCh37 |
193 | 397 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000652295.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 1, 2020 | RCV000836176.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 18, 2018 | RCV001336793.2 |
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
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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
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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
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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. |
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Likely benign
(Apr 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000978007.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Jun 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to ORAI1 deficiency
Myopathy, tubular aggregate, 2
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001468432.1
First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021 |
Comment:
ORAI1 NM_032790.3 exon 1 p.Ser34Arg (c.100A>C): This variant has not been reported in the literature in association with human disease, but is present in 0.1% … (more)
ORAI1 NM_032790.3 exon 1 p.Ser34Arg (c.100A>C): This variant has not been reported in the literature in association with human disease, but is present in 0.1% (71/52582) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-122064747-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:541941). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies predict that this variant will impact the protein (Zhang 2019 PMID:31036819). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(Apr 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to ORAI1 deficiency
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001530288.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Myopathy, tubular aggregate, 2
Combined immunodeficiency due to ORAI1 deficiency
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000774163.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 34 of the ORAI1 protein (p.Ser34Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 34 of the ORAI1 protein (p.Ser34Arg). This variant is present in population databases (rs781829024, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541941). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects ORAI1 function (PMID: 31036819). 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)
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Uncertain significance
(Mar 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334790.19
First in ClinVar: Jun 08, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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not provided
(-)
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no classification provided
Method: phenotyping only
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Combined immunodeficiency due to ORAI1 deficiency
Myopathy, tubular aggregate, 2
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749978.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 02-15-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 02-15-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of the nose (present) , Autoimmunity (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormality of the liver (present) , Obesity (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-02-15
Testing laboratory interpretation: Uncertain significance
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction. | Zhang X | Nature communications | 2019 | PMID: 31036819 |
Text-mined citations for rs781829024 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.