ClinVar Genomic variation as it relates to human health
NM_001364905.1(LRBA):c.1399A>G (p.Met467Val)
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(7); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001364905.1(LRBA):c.1399A>G (p.Met467Val)
Variation ID: 287150 Accession: VCV000287150.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q31.3 4: 150908428 (GRCh38) [ NCBI UCSC ] 4: 151829580 (GRCh37) [ 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 Dec 6, 2016 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001364905.1:c.1399A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351834.1:p.Met467Val missense NM_001199282.1:c.1399A>G NM_001199282.2:c.1399A>G NP_001186211.2:p.Met467Val missense NM_001367550.1:c.1399A>G NP_001354479.1:p.Met467Val missense NM_006726.4:c.1399A>G NP_006717.2:p.Met467Val missense NC_000004.12:g.150908428T>C NC_000004.11:g.151829580T>C NG_032855.1:g.112070A>G LRG_1324:g.112070A>G LRG_1324t1:c.1399A>G LRG_1324p1:p.Met467Val - Protein change
- M467V
- Other names
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- Canonical SPDI
- NC_000004.12:150908427:T: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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0.00060 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00078
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146
Trans-Omics for Precision Medicine (TOPMed) 0.00203
The Genome Aggregation Database (gnomAD), exomes 0.00212
Exome Aggregation Consortium (ExAC) 0.00217
The Genome Aggregation Database (gnomAD) 0.00225
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 | ||
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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
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. |
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LRBA | - | - |
GRCh38 GRCh37 |
1986 | 2073 |
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. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 1, 2020 | RCV000275233.11 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000650433.31 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 1, 2023 | RCV000755561.32 |
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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to LRBA deficiency
Affected status: unknown
Allele origin:
paternal
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782643.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
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Likely benign
(Apr 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000340834.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Aug 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927385.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
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Uncertain significance
(Jan 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to LRBA deficiency
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001525229.1
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 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to LRBA deficiency
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604126.4
First in ClinVar: Dec 06, 2016 Last updated: Jan 05, 2022 |
Comment:
The LRBA c.1399A>G; p.Met467Val variant (rs116355217) is reported in the literature in an individual with common variable immunodeficiency that carried a second missense variant in … (more)
The LRBA c.1399A>G; p.Met467Val variant (rs116355217) is reported in the literature in an individual with common variable immunodeficiency that carried a second missense variant in LRBA (Maffucci 2016). The p.Met467Val variant is reported in ClinVar (Variation ID: 287150) and is found in the general population with an overall allele frequency of 0.22% (606/276772 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 467 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.163). Due to limited information, the clinical significance of the p.Met467Val variant is uncertain at this time. References: Maffucci et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016 Jun 13;7:220. (less)
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Uncertain significance
(Jun 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064861.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the LRBA gene demonstrated a sequence change, c.1399A>G, in exon 11 that results in an amino acid change, p.Met467Val. This sequence … (more)
DNA sequence analysis of the LRBA gene demonstrated a sequence change, c.1399A>G, in exon 11 that results in an amino acid change, p.Met467Val. This sequence change has been described in the gnomAD database with a frequency of 0.4% in the European sub-population (dbSNP rs116355217). The p.Met467Va sequence change has been reported in one patient with common variable immunodeficiency who also had a second missense variant present in the LRBA gene, however functional and/or segregation studies were not performed to clarify the clinical significance of this sequence change (PMID: 27379089). The p.Met467Val change affects a moderately conserved amino acid residue located in a domain of the LRBA protein that is known to be functional. The p.Met467Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Met467Val change remains unknown at this time. (less)
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Uncertain significance
(May 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to LRBA deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology
Accession: SCV002525559.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
The c.1399A>G variant is present in publicly available population databases like 1000 Genomes, EVS, ExAC and gnomAD, at a low frequency. The variant is not … (more)
The c.1399A>G variant is present in publicly available population databases like 1000 Genomes, EVS, ExAC and gnomAD, at a low frequency. The variant is not present in Indian Exome Database and our in-house exome database. The variant was previously reported to ClinVar (Accession: VCV000287150.24) with conflicitng interpretations of pathogencicity (Uncertain significance/likely benign/benign) in association with combined immunodeficiency due to LRBA deficiency. The variant was previously identified in similarly affected individuals (PMID: 27379089, 28956255) and reported to Human Genome Mutation Database (HGMD ID: CM167684). Predictions from different in-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. are contradictory, however these predictions were not confirmed by any published functional studies. (less)
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010646.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to LRBA deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000772278.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
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Likely benign
(Dec 01, 2023)
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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: SCV000892403.23
First in ClinVar: Mar 31, 2019 Last updated: May 12, 2024 |
Comment:
LRBA: BP4, BS2
Number of individuals with the variant: 13
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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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Multiple Presentations of LRBA Deficiency: a Single-Center Experience. | Kostel Bal S | Journal of clinical immunology | 2017 | PMID: 28956255 |
Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. | Maffucci P | Frontiers in immunology | 2016 | PMID: 27379089 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LRBA | - | - | - | - |
Text-mined citations for rs116355217 ...
HelpRecord last updated May 12, 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.