Variant summary: BTK c.763C>T (p.Arg255X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 178404 control chromosomes (gnomAD). c.763C>T has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (e.g. Fiorini 2004, Conley 2005, Chen 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000061.3(BTK):c.763C>T (p.Arg255Ter)
Germline
Classification
Help
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.
(11)
Help
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000061.3(BTK):c.763C>T (p.Arg255Ter)
Variation ID: 11363 Accession: VCV000011363.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101360581 (GRCh38) [ NCBI UCSC ] X: 100615569 (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 Feb 19, 2018 Oct 20, 2024 Mar 14, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000061.3:c.763C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000052.1:p.Arg255Ter nonsense NM_001287344.2:c.865C>T NP_001274273.1:p.Arg289Ter nonsense NM_001287345.2:c.763C>T NP_001274274.1:p.Arg255Ter nonsense NC_000023.11:g.101360581G>A NC_000023.10:g.100615569G>A NG_009616.1:g.30644C>T LRG_128:g.30644C>T LRG_128t1:c.763C>T LRG_128p1:p.Arg255Ter - Protein change
- R255*, R289*
- Other names
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- Canonical SPDI
- NC_000023.11:101360580: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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| BTK | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
718 | 897 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV000012116.21 | |
| Pathogenic (1) |
no assertion criteria provided
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Mar 19, 2013 | RCV000583310.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Oct 16, 2023 | RCV001221640.7 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2023 | RCV001269823.18 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked agammaglobulinemia
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001141971.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
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Pathogenic
(Jan 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked agammaglobulinemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361010.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: BTK c.763C>T (p.Arg255X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BTK c.763C>T (p.Arg255X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 178404 control chromosomes (gnomAD). c.763C>T has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (e.g. Fiorini 2004, Conley 2005, Chen 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Pathogenic
(Oct 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450104.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked agammaglobulinemia
Affected status: yes
Allele origin:
germline
|
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine
Accession: SCV003837562.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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X-linked agammaglobulinemia with growth hormone deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001393699.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg255*) in the BTK gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg255*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked agammaglobulinemia (PMID: 8162056, 27512878, 29503650, 30564228). This variant is also known as 895C>T. ClinVar contains an entry for this variant (Variation ID: 11363). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585137.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
BTK: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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X-linked agammaglobulinemia
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424381.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
|
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Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004169668.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31967259, 25525159, 33471103, 33083013, 32888943, 35729272, 32552675, 29424453, 27512878, 30564228, 29503650, 8162056) (less)
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: research
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X-linked agammaglobulinemia
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801182.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Mar 19, 2013)
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no assertion criteria provided
Method: clinical testing
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Autosomal agammaglobulinemia
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692188.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
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Pathogenic
(Jan 01, 1994)
|
no assertion criteria provided
Method: literature only
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AGAMMAGLOBULINEMIA, X-LINKED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032350.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 03, 2018 |
Comment on evidence:
In a patient with X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a C-to-T transition at position 895 of the BTK gene, resulting in … (more)
In a patient with X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a C-to-T transition at position 895 of the BTK gene, resulting in a stop codon at position 255 and a severely truncated protein lacking the remaining 404 amino acids, which include the SH2 and kinase domains. This patient and his brother have no detectable B-cells, confirming that the absence of the functional domains of Btk results in a classic XLA phenotype. (less)
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg255*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked agammaglobulinemia (PMID: 8162056, 27512878, 29503650, 30564228). This variant is also known as 895C>T. ClinVar contains an entry for this variant (Variation ID: 11363). For these reasons, this variant has been classified as Pathogenic.
Comment:
BTK: PVS1, PM2, PS4:Moderate
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31967259, 25525159, 33471103, 33083013, 32888943, 35729272, 32552675, 29424453, 27512878, 30564228, 29503650, 8162056)
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:
Variant summary: BTK c.763C>T (p.Arg255X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 178404 control chromosomes (gnomAD). c.763C>T has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (e.g. Fiorini 2004, Conley 2005, Chen 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg255*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked agammaglobulinemia (PMID: 8162056, 27512878, 29503650, 30564228). This variant is also known as 895C>T. ClinVar contains an entry for this variant (Variation ID: 11363). For these reasons, this variant has been classified as Pathogenic.
Comment:
BTK: PVS1, PM2, PS4:Moderate
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31967259, 25525159, 33471103, 33083013, 32888943, 35729272, 32552675, 29424453, 27512878, 30564228, 29503650, 8162056)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots. | Collins CJ | Frontiers in immunology | 2018 | PMID: 30564228 |
| Dried Blood Spots, an Affordable Tool to Collect, Ship, and Sequence gDNA from Patients with an X-Linked Agammaglobulinemia Phenotype Residing in a Developing Country. | Segundo GRS | Frontiers in immunology | 2018 | PMID: 29503650 |
| Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015). | Chen XF | Medicine | 2016 | PMID: 27512878 |
| Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study. | Tóth B | Molecular immunology | 2009 | PMID: 19419768 |
| X-linked agammaglobulinemia: report on a United States registry of 201 patients. | Winkelstein JA | Medicine | 2006 | PMID: 16862044 |
| Genetic analysis of patients with defects in early B-cell development. | Conley ME | Immunological reviews | 2005 | PMID: 15661032 |
| BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia. | Fiorini M | Human mutation | 2004 | PMID: 14974089 |
| Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. | Bradley LA | Human molecular genetics | 1994 | PMID: 8162056 |
Text-mined citations for rs128621193 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.