Submissions for variant NM_000061.3(BTK):c.1684C>T (p.Arg562Trp)

dbSNP: rs128621204

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816209	SCV000956706	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2024-09-01	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 562 of the BTK protein (p.Arg562Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 7880320, 11742281, 16951917, 17765309, 19904586). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11383). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012136	SCV006074413	pathogenic	X-linked agammaglobulinemia	2025-04-23	criteria provided, single submitter	clinical testing	Variant summary: BTK c.1684C>T (p.Arg562Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183615 control chromosomes. c.1684C>T has been observed in multiple individuals affected with X-Linked Agammaglobulinemia (example, Hagemann_1994, Vorechovsky_1995, Wattanasirichaigoon_2006, Chan_2006, Conley_1994, Danielian_2003, Lopez-Herrera_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15661032, 16160918, 7849697, 9545398, 12655572, 7880320, 9445504, 11742281, 11809909, 12405164, 7809124, 7711734, 16712653, 16951917, 17765309, 17967562). ClinVar contains an entry for this variant (Variation ID: 11383). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000012136	SCV000032370	pathogenic	X-linked agammaglobulinemia	1994-10-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581337	SCV000692198	pathogenic	Autosomal recessive agammaglobulinemia 1	2011-08-31	no assertion criteria provided	clinical testing