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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 3, 2023
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:: RCV000692851.16

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 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
SCV000820696	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19419768, 19904586, 7711734, 8938104, 9545398, 11742281, 12405164, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000820696

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (8)
[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

Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.

Tóth B, Volokha A, Mihas A, Pac M, Bernatowska E, Kondratenko I, Polyakov A, Erdos M, Pasic S, Bataneant M, Szaflarska A, Mironska K, Richter D, Stavrik K, Avcin T, Márton G, Nagy K, Dérfalvi B, Szolnoky M, Kalmár A, Belevtsev M, Guseva M, et al.

Mol Immunol. 2009 Jun;46(10):2140-6. doi: 10.1016/j.molimm.2009.03.012. Epub 2009 May 5.

PubMed [citation]

PMID:: 19419768

Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia.

Lee PP, Chen TX, Jiang LP, Chan KW, Yang W, Lee BW, Chiang WC, Chen XY, Fok SF, Lee TL, Ho MH, Yang XQ, Lau YL.

J Clin Immunol. 2010 Jan;30(1):121-31. doi: 10.1007/s10875-009-9341-5. Epub 2009 Nov 11.

PubMed [citation]

PMID:: 19904586

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000820696.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 509 of the BTK protein (p.Met509Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (XLA) (PMID: 12405164, 19419768, 19904586). This variant is also known as 1658T>C. ClinVar contains an entry for this variant (Variation ID: 571649). 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 disrupts the p.Met509 amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID: 7711734, 8938104, 9545398, 11742281, 12405164), which suggests that this may be a clinically significant amino acid residue. 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: Nov 24, 2024

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