ClinVar Miner

Submissions for variant NM_000061.3(BTK):c.215dup (p.Asn72fs)

dbSNP: rs886041148
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000317789 SCV000329168 pathogenic not provided 2018-02-09 criteria provided, single submitter clinical testing The c.215dupA pathogenic variant in the BTK gene has been reported previously in association with X-linked agammaglobulinemia (XLA) (Gaspar et al., 1995; Yip et al., 2000; Daneilian et al., 2003; Lee et al., 2010). This duplication causes a frameshift starting with codon Asparagine 72, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Asn72LysfsX13. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.215dupA variant is not observed in large population cohorts (Lek et al., 2016). We interpret this variant as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781189 SCV000919071 pathogenic X-linked agammaglobulinemia 2018-08-10 criteria provided, single submitter clinical testing Variant summary: BTK c.215dupA (p.Asn72LysfsX13) is an insertion of an A into a run of seven As that results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 21737 control chromosomes (gnbomAD and publications). The variant, c.215dupA, has been reported in the literature in multiple individuals affected with X-linked Agammaglobulinemia (Gaspar_1995, Yip_2000, Danielian_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000811748 SCV000952031 pathogenic X-linked agammaglobulinemia with growth hormone deficiency 2020-10-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant has been observed in several individuals and families affected with X-linked agammaglobulinemia (PMID: 7633429, 12655572, 10737994). This variant is also known as 341insA, 341-347insA, 347_348insA, and N72fsX84 in the literature. ClinVar contains an entry for this variant (Variation ID: 279713). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn72Lysfs*13) in the BTK gene. It is expected to result in an absent or disrupted protein product.

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