X-101359324-C-T

Variant names:

• chrX-101359324-C-T
• rs1555978277
• NM_000061.3:c.863G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000061.3(BTK):​c.863G>A​(p.Arg288Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.65

Genes affected

BTK (HGNC:1133): (Bruton tyrosine kinase) The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain SH2 (size 96) in uniprot entity BTK_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BTK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0394 (above the threshold of 3.09). GenCC associations: The gene is linked to short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-101359324-C-T is Pathogenic according to our data. Variant chrX-101359324-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 492813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101359324-C-T is described in Lovd as [Pathogenic]. Variant chrX-101359324-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.863G>A	p.Arg288Gln	missense_variant	Exon 10 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.965G>A	p.Arg322Gln	missense_variant	Exon 10 of 19		NP_001274273.1
BTK	NM_001287345.2	c.863G>A	p.Arg288Gln	missense_variant	Exon 11 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.863G>A	p.Arg288Gln	missense_variant	Exon 10 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Feb 05, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTK c.863G>A; p.Arg288Gln variant (rs1555978277) is reported in the literature in numerous individuals with symptoms or a diagnosis of X-linked agammaglobulinemia (Abbott 2013, Conley 1998, Fiorini 2004, Futatani 2001, Lee 2010, Plebani 2002). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 492813). The arginine at codon 288 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Further, this variant occurs in the phosphotyrosine-binding pocket of a functional important SH2 domain and in vitro assays indicate that it disrupts binding to phosphorylated peptides (Tzeng 2000). Another variant at the same codon (p.Arg288Trp) has been reported in individuals with X-linked agammaglobulinemia and is considered pathogenic (Fiorini 2004, Plebani 2002, Tzeng 2000). Based on available information, the p.Arg288Gln variant is considered to be pathogenic. References: Abbott JK et al. Coding-region alterations in BTK do not universally cause X-linked agammaglobulinemia. J Allergy Clin Immunol. 2013 Nov;132(5):1246-8. Conley ME et al. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998 May;62(5):1034-43. Fiorini M et al. BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia. Hum Mutat. 2004 Mar;23(3):286. Futatani T et al. Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females. Br J Haematol. 2001 Jul;114(1):141-9. Lee PP et al. Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia. J Clin Immunol. 2010 Jan;30(1):121-31. Plebani A et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002 Sep;104(3):221-30. Tzeng SR et al. Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia. Protein Sci. 2000 Dec;9(12):2377-85. -

Autosomal recessive agammaglobulinemia 1 Pathogenic:1

Mar 03, 2010

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BTK function (PMID: 11206059). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect by abolishing the SH2 domain's binding affinity to receptor tyrosine kinase (PMID: 11206059); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24001798, 14974089, 30273710, 9545398, 12487187, 27091141, 24716070, 26960951, 16297664, 25616435, 29202590, 29424453, 11206059) -

X-linked agammaglobulinemia Pathogenic:1

Nov 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BTK c.863G>A (p.Arg288Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183437 control chromosomes (gnomAD). c.863G>A has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (e.g. Chen_2016, Conley_1998, Esenboga_2018, Plebani_2002). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate that the variant located in the phosphotyrosine binding site of the BTK SH2 domain results in total loss of the peptide binding affinity (Tzeng_2000). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;.;H
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	.;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.87
MutPred		0.88		Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);.;Loss of MoRF binding (P = 0.0423);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555978277; hg19: chrX-100614312; COSMIC: COSV58124345; COSMIC: COSV58124345;