NM_032790.4(ORAI1):c.290C>G (p.Ser97Cys) AND Myopathy, tubular aggregate, 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 4, 2022
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:: RCV000509049.3

Allele description

NM_032790.4(ORAI1):c.290C>G (p.Ser97Cys)

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.290C>G (p.Ser97Cys)

HGVS:

NC_000012.12:g.121627037C>G
NG_007500.1:g.5463C>G
NG_187556.1:g.728C>G
NM_032790.4:c.290C>GMANE SELECT
NP_116179.2:p.Ser97Cys
NP_116179.2:p.Ser97Cys
LRG_93t1:c.290C>G
LRG_93:g.5463C>G
LRG_93p1:p.Ser97Cys
NM_032790.3:c.290C>G

Protein change:

S97C; SER97CYS

Links:

OMIM: 610277.0008; dbSNP: rs1555322610

NCBI 1000 Genomes Browser:

rs1555322610

Observations:

Condition(s)

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
SCV000606831	OMIM	no assertion criteria provided	Pathogenic (Oct 4, 2017)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002579491	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000606831

OMIM

no assertion criteria provided

Pathogenic
(Oct 4, 2017)

germline

literature only

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

SCV002579491

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 4, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A novel gain-of-function mutation in ORAI1 causes late-onset tubular aggregate myopathy and congenital miosis.

Garibaldi M, Fattori F, Riva B, Labasse C, Brochier G, Ottaviani P, Sacconi S, Vizzaccaro E, Laschena F, Romero NB, Genazzani A, Bertini E, Antonini G.

Clin Genet. 2017 May;91(5):780-786. doi: 10.1111/cge.12888. Epub 2016 Nov 23.

PubMed [citation]

PMID:: 27882542

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

Details of each submission

From OMIM, SCV000606831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a father and his 2 adult children, of Italian descent, with autosomal dominant tubular aggregate myopathy-2 (TAM2; 615883), Garibaldi et al. (2017) identified a heterozygous c.290C-G transversion (c.290C-G, NM_032790.3) in the ORAI1 gene, resulting in a ser97-to-cys (S97C) substitution at a highly conserved residue in the M1 domain. The mutation was not found in the ExAC or Exome Variant Server database. In vitro functional expression studies in HEK293 cells showed that the variant resulted in increased rate of calcium entry, consistent with constitutive activation of the CRAC channel and a gain-of-function effect. Myotubes derived from 1 of the patients showed a similar increase in calcium entry and increased spontaneous oscillations compared to controls.

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

From MGZ Medical Genetics Center, SCV002579491.1

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

#	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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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