Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003513687 | SCV004300163 | likely pathogenic | X-linked agammaglobulinemia with growth hormone deficiency | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 454 of the BTK protein (p.His454Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with agammaglobulinemia (PMID: 11472359, 19904586; Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 28359783). This variant disrupts the p.His454 amino acid residue in BTK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27512878). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Clinical Genetics Laboratory, |
RCV004697302 | SCV005197347 | likely pathogenic | not provided | 2023-12-07 | criteria provided, single submitter | clinical testing |