ClinVar Miner

Submissions for variant NM_000061.3(BTK):c.1252T>C (p.Tyr418His)

gnomAD frequency: 0.00029  dbSNP: rs144079566
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000914387 SCV001059561 benign X-linked agammaglobulinemia with growth hormone deficiency 2024-01-23 criteria provided, single submitter clinical testing
Mendelics RCV000990917 SCV001141970 likely benign X-linked agammaglobulinemia 2019-05-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818852 SCV002069409 benign not specified 2021-09-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003902932 SCV004722903 likely benign BTK-related condition 2023-03-20 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP)- HUVH-VHIR, Vall d'Hebron University Hospital RCV003768811 SCV004022316 likely risk allele Common variable immunodeficiency no assertion criteria provided clinical testing This variant has been reported to be a minimally hypomorphic mutation in BTK resulting in reduced B cell numbers but no clinical disease (PMID: 18241230). In a patient with XLA carrying the p.Tyr418His variant, BTK expression has been studied showing a reduced expression compared to healthy controls (PMID: 11472359). We found the variant in an adult female patient with a clinical diagnosis of common variable immunodeficiency (CVID). The patient had skewed X chromosome inactivation in which the His418 allele (alternative allele) was predominantly expressed. The allele frequency of the variant is 0.0002685 (gnomad v3.2.1), greater than expected to be causing X-linked Agammaglobulinemia (OMIM: 300755). That's the reason why this variant may be considered Likely Benign for XLA. However, based on the reported functional evidence of this variant it can be considered as a risk allele for CVID and eventually for XLA.

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