ClinVar Genomic variation as it relates to human health
NM_001364905.1(LRBA):c.8024C>T (p.Thr2675Ile)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001364905.1(LRBA):c.8024C>T (p.Thr2675Ile)
Variation ID: 497404 Accession: VCV000497404.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q31.3 4: 150286028 (GRCh38) [ NCBI UCSC ] 4: 151207180 (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 Apr 2, 2018 May 1, 2024 Oct 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001364905.1:c.8024C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351834.1:p.Thr2675Ile missense NM_001199282.2:c.8021C>T NP_001186211.2:p.Thr2674Ile missense NM_001367550.1:c.8039C>T NP_001354479.1:p.Thr2680Ile missense NM_006726.4:c.8057C>T NP_006717.2:p.Thr2686Ile missense NC_000004.12:g.150286028G>A NC_000004.11:g.151207180G>A NG_032855.1:g.734470C>T LRG_1324:g.734470C>T LRG_1324t1:c.8024C>T LRG_1324p1:p.Thr2675Ile - Protein change
- T2686I, T2674I, T2675I, T2680I
- Other names
- p.Thr2686Ile
- Canonical SPDI
- NC_000004.12:150286027:G:A
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00043
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Exome Aggregation Consortium (ExAC) 0.00050
The Genome Aggregation Database (gnomAD) 0.00067
Trans-Omics for Precision Medicine (TOPMed) 0.00069
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 |
1985 | 2072 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2022 | RCV000591776.6 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2022 | RCV000650420.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 11, 2021 | RCV002530980.2 |
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
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
(Oct 10, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000701890.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Aug 10, 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: SCV000927371.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
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Uncertain significance
(Oct 19, 2020)
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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:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769394.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 31432443, PMID: 28473463). (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine (exon 54). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0504 - Same amino acid change has been observed in a mammal. (N) 0600 - Variant is located in an annotated domain or motif (WD40 repeat; NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance (ClinVar) and as likely benign (LOVD). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Uncertain significance
(Oct 25, 2022)
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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: SCV000772265.6
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2686 of the LRBA protein (p.Thr2686Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2686 of the LRBA protein (p.Thr2686Ile). This variant is present in population databases (rs202244838, gnomAD 0.08%), 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 LRBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 497404). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRBA protein function. 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 30, 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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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001468383.2
First in ClinVar: Jan 09, 2021 Last updated: May 06, 2023 |
Comment:
LRBA NM_006726.4 exon 55 p.Thr2686Ile (c.8057C>T): This variant has not been reported in the literature but is present in 0.08% (79/92680) of European alleles in … (more)
LRBA NM_006726.4 exon 55 p.Thr2686Ile (c.8057C>T): This variant has not been reported in the literature but is present in 0.08% (79/92680) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/4-151207180-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:497404). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. 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
(Mar 16, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227029.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4
Number of individuals with the variant: 2
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Uncertain significance
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003633287.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.8057C>T (p.T2686I) alteration is located in exon 55 (coding exon 54) of the LRBA gene. This alteration results from a C to T substitution … (more)
The c.8057C>T (p.T2686I) alteration is located in exon 55 (coding exon 54) of the LRBA gene. This alteration results from a C to T substitution at nucleotide position 8057, causing the threonine (T) at amino acid position 2686 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Combined immunodeficiency due to LRBA deficiency
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228735.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 06-16-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 06-16-2019 by Lab 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:
Hypermetropia (present) , Myopia (present) , Hyperacusis (present) , Abnormal oral cavity morphology (present) , Hypopigmentation of the skin (present) , Hypercholesterolemia (present) , Asthma … (more)
Hypermetropia (present) , Myopia (present) , Hyperacusis (present) , Abnormal oral cavity morphology (present) , Hypopigmentation of the skin (present) , Hypercholesterolemia (present) , Asthma (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Premature birth (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-06-16
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 Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects. | Cagdas D | Journal of clinical immunology | 2019 | PMID: 31432443 |
Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes. | Johnson MB | Diabetes | 2017 | PMID: 28473463 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LRBA | - | - | - | - |
Text-mined citations for rs202244838 ...
HelpRecord last updated May 01, 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.