NM_032790.4(ORAI1):c.259A>G (p.Lys87Glu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 18, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003791801.2

Allele description [Variation Report for NM_032790.4(ORAI1):c.259A>G (p.Lys87Glu)]

NM_032790.4(ORAI1):c.259A>G (p.Lys87Glu)

Genes:

LOC130008987:ATAC-STARR-seq lymphoblastoid silent region 4981 [Gene]
ORAI1:ORAI calcium release-activated calcium modulator 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_032790.4(ORAI1):c.259A>G (p.Lys87Glu)

HGVS:

NC_000012.12:g.121627006A>G
NG_007500.1:g.5432A>G
NG_187556.1:g.697A>G
NM_032790.4:c.259A>GMANE SELECT
NP_116179.2:p.Lys87Glu
NP_116179.2:p.Lys87Glu
LRG_93t1:c.259A>G
LRG_93:g.5432A>G
LRG_93p1:p.Lys87Glu
NC_000012.11:g.122064912A>G
NM_032790.3:c.259A>G
NR_186857.1:n.477A>G

Protein change:

K87E

Molecular consequence:

NM_032790.4:c.259A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_186857.1:n.477A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Combined immunodeficiency due to ORAI1 deficiency
Synonyms:: Immune dysfunction with T-cell inactivation due to calcium entry defect 1; IMMUNODEFICIENCY 9
Identifiers:: MONDO: MONDO:0013007; MedGen: C2748568; Orphanet: 169090; Orphanet: 317428; OMIM: 612782

Name:: Myopathy, tubular aggregate, 2 (TAM2)
Identifiers:: MONDO: MONDO:0014383; MedGen: C4014557; OMIM: 615883

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004585684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23943619, 26809793, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004585684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 18, 2024)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1.

Derler I, Plenk P, Fahrner M, Muik M, Jardin I, Schindl R, Gruber HJ, Groschner K, Romanin C.

J Biol Chem. 2013 Oct 4;288(40):29025-34. doi: 10.1074/jbc.M113.501510. Epub 2013 Aug 13.

PubMed [citation]

PMID:: 23943619
PMCID:: PMC3790000

Orai1 pore residues control CRAC channel inactivation independently of calmodulin.

Mullins FM, Yen M, Lewis RS.

J Gen Physiol. 2016 Feb;147(2):137-52. doi: 10.1085/jgp.201511437. Erratum in: J Gen Physiol. 2016 Mar;147(3):289. doi: 10.1085/jgp.20151143701262016c.

PubMed [citation]

PMID:: 26809793
PMCID:: PMC4727942

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004585684.1

#	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 lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 87 of the ORAI1 protein (p.Lys87Glu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. 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 does not substantially affect ORAI1 function (PMID: 23943619, 26809793). 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.

#	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: Sep 29, 2024

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