ClinVar Miner

Submissions for variant NM_000061.3(BTK):c.777-1G>A

dbSNP: rs1603007942
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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 RCV000801814 SCV000941610 pathogenic X-linked agammaglobulinemia with growth hormone deficiency 2019-02-07 criteria provided, single submitter clinical testing This variant has been observed in individuals affected with X-linked agammaglobulinemia (PMID: 10844531, 19419768). This variant is also known as Intron 8-1G>A in the literature. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 8 of the BTK gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Illumina Laboratory Services, Illumina RCV001796233 SCV002034867 likely pathogenic X-linked agammaglobulinemia 2021-10-13 criteria provided, single submitter clinical testing The BTK c.777-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt the normal gene product. This variant has been reported in two unrelated male individuals affected with low serum immunoglobulin levels, recurrent infections and severely reduced levels of peripheral B-cells, with reduced expression of BTK noted in one individual (Kanegane et al. 2000; Toth et al. 2009). In addition, an alternative nucleotide change at the same position, c.777-1G>C, was reported in a hemizygous state in a male individual with X-linked agammaglobulinemia (Holinski-Feder et al. 1998). The variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggest the variant is rare. Based on the available evidence, the c.777-1G>A variant is classified as likely pathogenic for X-linked agammaglobulinemia.

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