ClinVar Miner

Submissions for variant NM_000061.3(BTK):c.1442G>C (rs1057519825)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781188 SCV000919070 uncertain significance not specified 2019-12-06 criteria provided, single submitter clinical testing BTK c.1442G>C (p.Cys481Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Loss of function variants resulting in a complete absence of BTK protein are considered to be pathognomic of disease in patients with X-linked agammaglobulinemia. The variant was absent in 183410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1442G>C has not, to our knowledge, been reported in the literature as a germline variant in individuals affected with X-linked Agammaglobulinemia. However, this variant and others resulting in a C481S BTK protein have been detected in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) who developed resistance to ibrutinib therapy (e.g. Ahn_2017, Albitar_2017, Burger_2016, Chiron_2014, Woyach_2014,2017). These reports do not provide unequivocal conclusions about association of the variant with X-linked Agammaglobulinemia. Several publications report experimental evidence that the variant impairs binding of ibrutinib, rescuing BTK signaling in cells treated with the drug (e.g. Chiron_2014, Chen_2018, Cheng_2014, Woyach_2014). However, no significant differences in downtream signaling were observed in DT40 (BTK-/-) chicken B cells transfected with wild type or C481S BTK in the absence of ibutinib (Woyach_2014). Thus, the variant's effects on the protein appear to be limited to ibrutinib binding, and these assays cannot be used to predict the consequences of the variant as a germline mutation. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was re-classified as uncertain significance for X-linked agammaglobulinemia although an actionable outcome in settings of CLL/MCL cannot be ruled out.
Invitae RCV001243610 SCV001416778 uncertain significance X-linked agammaglobulinemia with growth hormone deficiency 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 481 of the BTK protein (p.Cys481Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature as a germline variant in individuals with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 376203). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269707 SCV001449900 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000430045 SCV000505281 likely pathogenic Breast neoplasm 2014-12-26 no assertion criteria provided literature only

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