NM_000061.3(BTK):c.1526T>C (p.Met509Thr) AND X-linked agammaglobulinemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 18, 2020
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:: RCV004017718.1

Allele description [Variation Report for NM_000061.3(BTK):c.1526T>C (p.Met509Thr)]

NM_000061.3(BTK):c.1526T>C (p.Met509Thr)

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.1526T>C (p.Met509Thr)

HGVS:

NC_000023.11:g.101356092A>G
NG_009616.1:g.35133T>C
NM_000061.3:c.1526T>CMANE SELECT
NM_001287344.2:c.1628T>C
NM_001287345.2:c.1039-1398T>C
NP_000052.1:p.Met509Thr
NP_000052.1:p.Met509Thr
NP_001274273.1:p.Met543Thr
LRG_128t1:c.1526T>C
LRG_128:g.35133T>C
LRG_128p1:p.Met509Thr
NC_000023.10:g.100611080A>G
NM_000061.2:c.1526T>C

Protein change:

M509T

Links:

dbSNP: rs1569291644

NCBI 1000 Genomes Browser:

rs1569291644

Molecular consequence:

NM_001287345.2:c.1039-1398T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000061.3:c.1526T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287344.2:c.1628T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848520	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 18, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27512878, 12405164, 19419768, 19904586, 16712653, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848520

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 18, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).

Chen XF, Wang WF, Zhang YD, Zhao W, Wu J, Chen TX.

Medicine (Baltimore). 2016 Aug;95(32):e4544. doi: 10.1097/MD.0000000000004544.

PubMed [citation]

PMID:: 27512878
PMCID:: PMC4985333

XLA patients with BTK splice-site mutations produce low levels of wild-type BTK transcripts.

Noordzij JG, de Bruin-Versteeg S, Hartwig NG, Weemaes CM, Gerritsen EJ, Bernatowska E, van Lierde S, de Groot R, van Dongen JJ.

J Clin Immunol. 2002 Sep;22(5):306-18.

PubMed [citation]

PMID:: 12405164

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Met509Thr variant in BTK has been reported in at least 4 individuals with X-linked agammaglobulinemia (XLA; Chan 2006 PMID: 16712653, Noordzij 2002 PMID: 12405164, Toth 2009 PMID: 19419768, Chen 2016 PMID: 27512878, Lee 2010 PMID: 19904586). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 571649) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant lies in the alpha-helix E region of the protein and the methionine (Met) residue in codon 509 is conserved in protein-tyrosine kinases and is thought to be critical for the structure and stability of the catalytic site of the enzyme (Vorechovsky 1995 PMID: 7711734, Mattsson 1996 PMID: 8885720). Additional variants involving this codon (p.Met509Ile and p.Met509Val) have been identified in individuals with XLA (Vorechovsky 1995 PMID: 7711734, Farrar 1996 PMID: 8938104, Conley 1998 PMID: 9545398, Kanegane 2001 PMID: 11742281, Noordzij 2002 PMID: 12405164). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for X-linked agammaglobulinemia. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3, PM1.

#	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: Nov 24, 2024

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