NM_000061.3(BTK):c.1763G>T (p.Trp588Leu) AND X-linked agammaglobulinemia with growth hormone deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 24, 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:: RCV001984261.6

Allele description [Variation Report for NM_000061.3(BTK):c.1763G>T (p.Trp588Leu)]

NM_000061.3(BTK):c.1763G>T (p.Trp588Leu)

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.1763G>T (p.Trp588Leu)

HGVS:

NC_000023.11:g.101353339C>A
NG_009616.1:g.37886G>T
NG_011734.1:g.631G>T
NM_000061.3:c.1763G>TMANE SELECT
NM_001287344.2:c.1865G>T
NM_001287345.2:c.1235G>T
NP_000052.1:p.Trp588Leu
NP_001274273.1:p.Trp622Leu
NP_001274274.1:p.Trp412Leu
LRG_128:g.37886G>T
NC_000023.10:g.100608327C>A

Protein change:

W412L

Links:

dbSNP: rs1603001805

NCBI 1000 Genomes Browser:

rs1603001805

Molecular consequence:

NM_000061.3:c.1763G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287344.2:c.1865G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287345.2:c.1235G>T - 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
SCV002280421	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 24, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14974089, 17045652, 26931785, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002280421

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 24, 2020)

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

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

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002280421.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp588 amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID: 14974089, 17045652, 26931785), which suggests that this may be a clinically significant amino acid residue. 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. This variant has not been reported in the literature in individuals with BTK-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with leucine at codon 588 of the BTK protein (p.Trp588Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine.

#	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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