Submissions for variant NM_000061.3(BTK):c.83G>A (p.Arg28His)

dbSNP: rs128620185

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427660	SCV000512428	pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing	The R28H missense variant in the BTK gene has been reported previously in association with X-linked agammaglobulinemia (Chen et al., 2016; Velickovic et la., 2004; Vihinen et al., 1995). The R28H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R28H variant is a conservative amino acid substitution; yet, this substitution occurs at a position that is conserved across species in the Inositol-1,3,4,5-Tetrakisphosphate (IP4) binding site of the pleckstrin homology (PH) domain. In silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies show that R28H destroys or decreases the protein's IP4 binding capacity compared to wild type (Fukuda et al., 1996; Rawlings et al., 1995). Missense variants in the same (R28C/S/P/L) and nearby residues (F25S, K27R, L31P, L32S/W, R33P/I) have been reported in the Human Gene Mutation Database in association with X-linked agammaglobulinemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Thus, the presence of the pathogenic R28H variant is consistent with the diagnosis in this patient.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819061	SCV000959703	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 28 of the BTK protein (p.Arg28His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 9143921, 11668622, 19904586). This variant is also known as 215G>A. ClinVar contains an entry for this variant (Variation ID: 11348). 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. Experimental studies have shown that this missense change affects BTK function (PMID: 8939985). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000427660	SCV001245920	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
3billion	RCV000012101	SCV002521306	pathogenic	X-linked agammaglobulinemia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011348). Different missense changes at the same codon (p.Arg28Cys, p.Arg28Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000946996, VCV001075550). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000012101	SCV003807709	pathogenic	X-linked agammaglobulinemia	2022-10-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PP3 supporting
OMIM	RCV000012101	SCV000032335	pathogenic	X-linked agammaglobulinemia	2001-07-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583846	SCV000692183	pathogenic	Autosomal recessive agammaglobulinemia 1	2007-03-13	no assertion criteria provided	clinical testing