Submissions for variant NM_000061.3(BTK):c.1328T>C (p.Ile443Thr)

gnomAD frequency: 0.00001  dbSNP: rs782133950

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231977	SCV001404516	uncertain significance	X-linked agammaglobulinemia with growth hormone deficiency	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 443 of the BTK protein (p.Ile443Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs782133950, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with BTK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
PreventionGenetics, part of Exact Sciences	RCV003398986	SCV004104677	uncertain significance	BTK-related disorder	2023-07-31	criteria provided, single submitter	clinical testing	The BTK c.1328T>C variant is predicted to result in the amino acid substitution p.Ile443Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0052% of alleles in individuals of South Asian descent in gnomAD, including one hemizygous individual of European (non-Finish descent) (http://gnomad.broadinstitute.org/variant/X-100611793-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.