ClinVar Miner

Submissions for variant NM_000061.3(BTK):c.337G>A (p.Val113Ile)

dbSNP: rs2147443453
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002022737 SCV002288711 uncertain significance X-linked agammaglobulinemia with growth hormone deficiency 2022-06-09 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 113 of the BTK protein (p.Val113Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked agammaglobulinemia (PMID: 33815962). 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 not expected to disrupt BTK protein function. This variant disrupts the p.Val113 amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID: 9545398, 12217331), 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003738125 SCV004564396 uncertain significance not provided 2023-02-24 criteria provided, single submitter clinical testing The BTK c.337G>A; p.Val113Ile variant (rs2147443453), is reported in the literature in an individual affected with X-linked agammaglobulinemia (Yildirim 2021). This variant is also reported in ClinVar (Variation ID: 1503280) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.338T>A, p.Val113Asp; c.337G>T, p. Val113Phe) have been reported in individuals with X-linked agammaglobulinemia (Conley 1998, Plebani 2002). Computational analyses are uncertain whether the p.Val113Ile variant is neutral or deleterious (REVEL: 0.387). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Conley ME et al. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998 May;62(5):1034-43. PMID: 9545398. Plebani A et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002 Sep;104(3):221-30. PMID: 12217331. Yildirim I et al. X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up. Am J Clin Exp Immunol. 2021 Feb 15;10(1):37-43. Erratum in: Am J Clin Exp Immunol. 2021 Aug 15;10(2):63-64. PMID: 33815962.

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