Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
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, |
RCV001027548 | SCV001190118 | likely pathogenic | Inherited Immunodeficiency Diseases | 2019-01-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001873186 | SCV002139301 | uncertain significance | X-linked agammaglobulinemia with growth hormone deficiency | 2022-11-14 | criteria provided, single submitter | clinical testing | 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. 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 introduces a premature termination codon (PMID: 12405164). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 632730). This variant is also known as 99G>A and 372G>A. 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. This variant is not present in population databases (gnomAD no frequency). 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 disrupted protein product. |
| Molecular Diagnostic Laboratory, |
RCV000780072 | SCV004698007 | likely pathogenic | X-linked agammaglobulinemia | no assertion criteria provided | clinical testing |