Submissions for variant NM_000061.3(BTK):c.863G>A (p.Arg288Gln)

dbSNP: rs1555978277

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657848	SCV000779605	pathogenic	not provided	2023-12-18	criteria provided, single submitter	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690161	SCV000817839	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2024-10-27	criteria provided, single submitter	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001062	SCV001158183	pathogenic	not specified	2019-02-05	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192716	SCV001361011	pathogenic	X-linked agammaglobulinemia	2019-11-11	criteria provided, single submitter	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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000584540	SCV000692189	pathogenic	Autosomal recessive agammaglobulinemia 1	2010-03-03	no assertion criteria provided	clinical testing