NM_000061.3(BTK):c.1762T>C (p.Trp588Arg) AND X-linked agammaglobulinemia with growth hormone deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 12, 2022
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:: RCV003513680.2

Allele description [Variation Report for NM_000061.3(BTK):c.1762T>C (p.Trp588Arg)]

NM_000061.3(BTK):c.1762T>C (p.Trp588Arg)

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.1762T>C (p.Trp588Arg)

HGVS:

NC_000023.11:g.101353340A>G
NG_009616.1:g.37885T>C
NG_011734.1:g.630T>C
NM_000061.3:c.1762T>CMANE SELECT
NM_001287344.2:c.1864T>C
NM_001287345.2:c.1234T>C
NP_000052.1:p.Trp588Arg
NP_000052.1:p.Trp588Arg
NP_001274273.1:p.Trp622Arg
NP_001274274.1:p.Trp412Arg
LRG_128t1:c.1762T>C
LRG_128:g.37885T>C
LRG_128p1:p.Trp588Arg
NC_000023.10:g.100608328A>G
NM_000061.2:c.1762T>C

Protein change:

W412R

Molecular consequence:

NM_000061.3:c.1762T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287344.2:c.1864T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287345.2:c.1234T>C - 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
SCV004300154	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17045652, 14974089, 26931785, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004300154

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 12, 2022)

germline

clinical testing

PubMed (4)
[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

Characterization of novel Bruton's tyrosine kinase gene mutations in Central European patients with agammaglobulinemia.

Kristufek D, Aspalter RM, Eibl MM, Wolf HM.

Mol Immunol. 2007 Mar;44(7):1639-43. Epub 2006 Oct 12.

PubMed [citation]

PMID:: 17045652

BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia.

Fiorini M, Franceschini R, Soresina A, Schumacher RF, Ugazio AG, Rossi P, Plebani A, Notarangelo LD.

Hum Mutat. 2004 Mar;23(3):286.

PubMed [citation]

PMID:: 14974089

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004300154.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 588 of the BTK protein (p.Trp588Arg). This missense change has been observed in individual(s) with agammaglobulinemia (PMID: 17045652). 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. This variant disrupts the p.Trp588 amino acid residue in BTK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14974089, 26931785). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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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