Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002234233 | SCV000933896 | likely pathogenic | Oligosynaptic infertility; 46,XY disorder of sex development | 2018-12-02 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Arg84 amino acid residue in NR5A1. Other variant(s) that disrupt this residue have been observed in individuals with NR5A1-related conditions (PMID: 24434652), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change results in reduced DNA binding ability and decreased transcriptional activation (PMID: 17694559). This variant has been reported in individuals affected with 46,XY disorders of sex development (PMID: 17694559, 27899157). This variant is present in population databases (rs375469069, ExAC 0.002%). This sequence change replaces arginine with histidine at codon 84 of the NR5A1 protein (p.Arg84His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. |
Kasturba Medical College, |
RCV001805860 | SCV002053807 | likely pathogenic | 46,XY sex reversal 3 | criteria provided, single submitter | clinical testing | ||
Prevention |
RCV003411746 | SCV004111582 | pathogenic | NR5A1-related disorder | 2023-05-07 | criteria provided, single submitter | clinical testing | The NR5A1 c.251G>A variant is predicted to result in the amino acid substitution p.Arg84His. This variant has been reported to have arise de novo in individuals with 46,XY disorders of sex development (Kohler et al 2008. PubMed ID: 17694559; Eggers S et al 2016. PubMed ID: 27899157; Sreenivasan R et al 2018. PubMed ID: 30067310; Ochoa MF et al 2020. PubMed ID: 34095474). Functional studies of this variant revealed impaired transcriptional activation of NR5A1-responsive target genes (Kohler et al 2008. PubMed ID: 17694559; Robevska et al. 2018. PubMed ID: 29027299; Sreenivasan R et al 2018. PubMed ID: 30067310) This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-127262988-C-T). An alternative variant at the same amino acid (p.Arg84Cys) has also been reported in patients with 46,XY DSD (Reuter et al. 2007. PubMed ID: 17656604). This variant is interpreted as pathogenic. |