Submissions for variant NM_000061.3(BTK):c.905G>T (p.Gly302Val)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003511518	SCV004305480	uncertain significance	X-linked agammaglobulinemia with growth hormone deficiency	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 302 of the BTK protein (p.Gly302Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of agammaglobulinemia (Invitae). 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 with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly302 amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID: 7627183, 15024743, 29202590; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.