Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clinical Molecular Genetics Laboratory, |
RCV000582454 | SCV000692290 | pathogenic | Congenital adrenal hypoplasia, X-linked | 2017-10-27 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002530827 | SCV003339842 | likely pathogenic | Congenital adrenal hypoplasia, X-linked; 46,XY sex reversal 2 | 2022-04-06 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 1 of the NR0B1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant has not been reported in the literature in individuals affected with NR0B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 492857). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the NR0B1 protein. Other variant(s) that disrupt this region (p.Gln395*, p.Asp459Glyfs*3, p.Ser431Ilefs*6) have been observed in individuals with NR0B1-related conditions (PMID: 7609262, 8855822). This suggests that this may be a clinically significant region of the protein. 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. |