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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
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:: RCV000690161.7

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 with growth hormone deficiency (IGHD3)
Synonyms:: IGHD III; Isolated growth hormone deficiency type 3; Growth hormone deficiency with hypogammaglobulinemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010615; MedGen: C0472813; Orphanet: 631; OMIM: 307200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000817839	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9545398, 11472359, 12217331, 15661032, 11206059, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000817839

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

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

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

Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females.

Futatani T, Watanabe C, Baba Y, Tsukada S, Ochs HD.

Br J Haematol. 2001 Jul;114(1):141-9.

PubMed [citation]

PMID:: 11472359

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000817839.6

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 288 of the BTK protein (p.Arg288Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 9545398, 11472359, 12217331, 15661032). ClinVar contains an entry for this variant (Variation ID: 492813). 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 expected to disrupt BTK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BTK function (PMID: 11206059). For these reasons, this variant has been 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 16, 2024

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