VCV002584489.3 - ClinVar

NM_001364905.1(LRBA):c.1933C>T (p.Arg645Ter)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001364905.1(LRBA):c.1933C>T (p.Arg645Ter)

Variation ID: 2584489 Accession: VCV002584489.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q31.3 4: 150897810 (GRCh38) [ NCBI UCSC ] 4: 151818962 (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	Oct 21, 2023	Apr 6, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001364905.1:c.1933C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001351834.1:p.Arg645Ter	nonsense
NM_001199282.2:c.1933C>T	NP_001186211.2:p.Arg645Ter	nonsense
NM_001367550.1:c.1933C>T	NP_001354479.1:p.Arg645Ter	nonsense
NM_006726.4:c.1933C>T	NP_006717.2:p.Arg645Ter	nonsense
NC_000004.12:g.150897810G>A
NC_000004.11:g.151818962G>A
NG_032855.1:g.122688C>T
LRG_1324:g.122688C>T
LRG_1324t1:c.1933C>T	LRG_1324p1:p.Arg645Ter

... more HGVS ... less HGVS

Protein change

R645*

Other names

Canonical SPDI

NC_000004.12:150897809: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.
LRBA		-	-	GRCh38 GRCh37	2017	2110

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.
Combined immunodeficiency due to LRBA deficiency	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV003335929.5

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.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	IMMUNODEFICIENCY, COMMON VARIABLE, 8, WITH AUTOIMMUNITY Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046270.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This nonsense variant found in exon 15 of 58 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more) This nonsense variant found in exon 15 of 58 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in a 16 year old male patient with recurrent common variable immunodeficiency symptoms including chronic diarrhea, interstitial pneumonia, cutaneous granulomatous lesions, hepatosplenomegaly, and finger clubbing. Additionally, immunoblot analysis performed for this patient showed absent LRBA protein expression (PMID: 32154999). Loss-of-function variation in LRBA is an established mechanism of disease (PMID: 32284663, 31883622). The c.1933C>T (p.Arg645Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/249840) and thus is presumed to be rare. Based on the available evidence, the c.1933C>T (p.Arg645Ter) variant is classified as Pathogenic. (less)
Pathogenic (May 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Combined immunodeficiency due to LRBA deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004641518.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 32154999‚ 26206937‚ 26768763 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with common variable immunodeficiency (PMID: … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with common variable immunodeficiency (PMID: 32154999). This variant is present in population databases (rs368167203, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg645*) in the LRBA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRBA are known to be pathogenic (PMID: 26206937, 26768763). (less)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined immunodeficiency due to LRBA deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806658.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024

Comment:

This nonsense variant found in exon 15 of 58 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in a 16 year old male patient with recurrent common variable immunodeficiency symptoms including chronic diarrhea, interstitial pneumonia, cutaneous granulomatous lesions, hepatosplenomegaly, and finger clubbing. Additionally, immunoblot analysis performed for this patient showed absent LRBA protein expression (PMID: 32154999). Loss-of-function variation in LRBA is an established mechanism of disease (PMID: 32284663, 31883622). The c.1933C>T (p.Arg645Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/249840) and thus is presumed to be rare. Based on the available evidence, the c.1933C>T (p.Arg645Ter) variant is classified as Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with common variable immunodeficiency (PMID: 32154999). This variant is present in population databases (rs368167203, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg645*) in the LRBA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRBA are known to be pathogenic (PMID: 26206937, 26768763).

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
Novel compound heterozygous stop-gain mutations of LRBA in a Vietnamese patient with Common Variable Immune Deficiency.	Phan ANL	Molecular genetics & genomic medicine	2020	PMID: 32154999
The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency.	Gámez-Díaz L	The Journal of allergy and clinical immunology	2016	PMID: 26768763
AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.	Lo B	Science (New York, N.Y.)	2015	PMID: 26206937

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001364905.1(LRBA):c.1933C>T (p.Arg645Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...