Submissions for variant NM_000061.3(BTK):c.862C>T (p.Arg288Trp)

dbSNP: rs128621194

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768159	SCV000898551	likely pathogenic	X-linked agammaglobulinemia; X-linked agammaglobulinemia with growth hormone deficiency	2021-11-22	criteria provided, single submitter	clinical testing	BTK NM_000061.2 exon 10 p.Arg288Trp (c.862C>T): This variant has been reported in the literature in at least 3 individuals with X-linked agammaglobulinemia (XLA), segregating with disease in at least 5 affected family members (Mensink 1984 PMID:6595200, deWeers 1994 PMID:8162018, Bradley 1998 PMID:8162056, Kanegane 2001 PMID:11742281, Lopez-Herrera 2008 PMID:17765309). However, individuals from 1 family exhibited significant clinical and immunological heterogenity (Mensink 1984 PMID:6595200, deWeers 1994 PMID:8162018, Bradley 1998 PMID:8162056). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:11366). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies also predict that this variant will impact the protein (Tzeng 2000 PMID:11206059, Lopez-Herrera 2008 PMID:17765309). Of note, a different variant at this same codon (p.Arg288Gln) has been reported in the literature in individuals with disease, supporting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384086	SCV001583470	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 288 of the BTK protein (p.Arg288Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 14974089, 15112668, 17765309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11366). 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). This variant disrupts the p.Arg288 amino acid residue in BTK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9545398, 12217331, 15661032). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000012119	SCV002059035	pathogenic	X-linked agammaglobulinemia	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011366, PMID:8162056, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 15112668, 17765309, 14974089, PS4_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000492813, PMID:9545398, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.915, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000012119	SCV000032353	pathogenic	X-linked agammaglobulinemia	2018-10-29	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701564	SCV001929848	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701564	SCV001957747	pathogenic	not provided		no assertion criteria provided	clinical testing