NM_000061.3(BTK):c.1901G>C (p.Trp634Ser) AND X-linked agammaglobulinemia with growth hormone deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 18, 2019
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:: RCV001057527.9

Allele description [Variation Report for NM_000061.3(BTK):c.1901G>C (p.Trp634Ser)]

NM_000061.3(BTK):c.1901G>C (p.Trp634Ser)

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.1901G>C (p.Trp634Ser)

HGVS:

NC_000023.11:g.101353201C>G
NG_009616.1:g.38024G>C
NG_011734.1:g.769G>C
NM_000061.3:c.1901G>CMANE SELECT
NM_001287344.2:c.2003G>C
NM_001287345.2:c.1373G>C
NP_000052.1:p.Trp634Ser
NP_001274273.1:p.Trp668Ser
NP_001274274.1:p.Trp458Ser
LRG_128t1:c.1901G>C
LRG_128:g.38024G>C
NC_000023.10:g.100608189C>G
NM_000061.2:c.1901G>C

Protein change:

W458S

Links:

dbSNP: rs1926352588

NCBI 1000 Genomes Browser:

rs1926352588

Molecular consequence:

NM_000061.3:c.1901G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287344.2:c.2003G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287345.2:c.1373G>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

Recent activity

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interleukin-1 receptor type 2 isoform 2 precursor [Mus musculus]
interleukin-1 receptor type 2 isoform 2 precursor [Mus musculus]
gi|6754330|ref|NP_034685.1|

Protein
Mus musculus EMSY, BRCA2-interacting transcriptional repressor (Emsy), transcrip...
Mus musculus EMSY, BRCA2-interacting transcriptional repressor (Emsy), transcript variant 4, mRNA
gi|124249083|ref|NM_172280.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001222025	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 18, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001222025

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 18, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001222025.5

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

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.Trp634¬†amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID:¬†27512878, 25777788), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with X-linked agammaglobulinemia (PMID:¬†12655572). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with serine at codon 634 of the BTK protein (p.Trp634Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine.

#	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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