Submissions for variant NM_000061.3(BTK):c.240G>A (p.Pro80=)

dbSNP: rs1569296295

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780072	SCV000917095	likely pathogenic	X-linked agammaglobulinemia	2018-03-21	criteria provided, single submitter	clinical testing	Variant summary: BTK c.240G>A (p.Pro80Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. Four predict the variant weakens a 5' donor site. An impact on splicing was confirmed by RT-PCR in patient cells which showed a mutant transcript that included 106 intronic nucleotides as the major transcript, whereas wild-type transcript levels were at <10% (Noordzij_2002). The variant was absent in 87702 control chromosomes. c.240G>A has been reported in the literature in individuals affected with X-linked Agammaglobulinemia, and in the uncle of a patient who appears to be unaffected or have mild disease (Conley_1998, Conley_2005, Noordzij_2002). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001027548	SCV001190118	likely pathogenic	Inherited Immunodeficiency Diseases	2019-01-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873186	SCV002139301	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change affects codon 80 of the BTK mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BTK protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with late-onset X-linked agammaglobulinemia with mild clinical phenotype (PMID: 9545398, 12405164, 15661032) . It has also been observed in an apparently unaffected male relative. It has also been observed to segregate with disease in related individuals. This variant is also known as 99G>A and 372G>A. ClinVar contains an entry for this variant (Variation ID: 632730). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of 106 nt from intron 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12405164). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory, Beijing Chigene Translational Medicine Research Center	RCV000780072	SCV004698007	likely pathogenic	X-linked agammaglobulinemia		no assertion criteria provided	clinical testing