NM_000061.3(BTK):c.863G>A (p.Arg288Gln) AND X-linked agammaglobulinemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 11, 2019
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:: RCV001192716.1

Allele description [Variation Report for NM_000061.3(BTK):c.863G>A (p.Arg288Gln)]

NM_000061.3(BTK):c.863G>A (p.Arg288Gln)

Gene:

BTK:Bruton tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000061.3(BTK):c.863G>A (p.Arg288Gln)

HGVS:

NC_000023.11:g.101359324C>T
NG_009616.1:g.31901G>A
NM_000061.3:c.863G>AMANE SELECT
NM_001287344.2:c.965G>A
NM_001287345.2:c.863G>A
NP_000052.1:p.Arg288Gln
NP_000052.1:p.Arg288Gln
NP_001274273.1:p.Arg322Gln
NP_001274274.1:p.Arg288Gln
LRG_128t1:c.863G>A
LRG_128:g.31901G>A
LRG_128p1:p.Arg288Gln
NC_000023.10:g.100614312C>T
NM_000061.2:c.863G>A

Protein change:

R288Q

Links:

dbSNP: rs1555978277

NCBI 1000 Genomes Browser:

rs1555978277

Molecular consequence:

NM_000061.3:c.863G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287344.2:c.965G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287345.2:c.863G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked agammaglobulinemia (XLA)
Synonyms:: IMMUNODEFICIENCY 1; Bruton's agammaglobulinemia; AGAMMAGLOBULINEMIA, X-LINKED, TYPE 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010421; MedGen: C0221026; Orphanet: 229717; Orphanet: 47; OMIM: 300755

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myeloid-associated differentiation marker [Homo sapiens]
myeloid-associated differentiation marker [Homo sapiens]
gi|589058155|ref|NP_001277122.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361011	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 11, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9545398, 11206059, 27512878, 29424453, 12217331 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001361011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 11, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in btk in patients with presumed X-linked agammaglobulinemia.

Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J.

Am J Hum Genet. 1998 May;62(5):1034-43.

PubMed [citation]

PMID:: 9545398
PMCID:: PMC1377085

Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia.

Tzeng SR, Pai MT, Lung FD, Wu CW, Roller PP, Lei B, Wei CJ, Tu SC, Chen SH, Soong WJ, Cheng JW.

Protein Sci. 2000 Dec;9(12):2377-85.

PubMed [citation]

PMID:: 11206059
PMCID:: PMC2144513

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361011.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: BTK c.863G>A (p.Arg288Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183437 control chromosomes (gnomAD). c.863G>A has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (e.g. Chen_2016, Conley_1998, Esenboga_2018, Plebani_2002). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate that the variant located in the phosphotyrosine binding site of the BTK SH2 domain results in total loss of the peptide binding affinity (Tzeng_2000). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024

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