Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV004555172 | SCV005044096 | pathogenic | 46,XY sex reversal 3 | 2021-11-10 | criteria provided, single submitter | clinical testing | The de novo c.841C>T (p.Arg281Cys) missense variant identified in exon 4 (of 7) of the NR5A1 gene has been reported as heterozygous in an adult individual with partially virilized 46, XY DSD [PMID: 31745530], and in an another unrelated adult individual with severe gonadal dysplasia [PMID: 33728612]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects a highly conserved residue (Arg281) located in the ligand-binding domain of the NR5A1 protein [PMID: 31745530] and is predicted deleterious by multiple in silico prediction tools (CADD score = 28.7, REVEL score = 0.855). A different missense variant (p.Arg281Pro) affecting the same p.Arg281 has been reported in a newborn with 46, XY DSD [PMID: 21163476]. In vitro functional analyses suggest that the c.841C>T (p.Arg281Cys) variant identified in this fetus as well as the c.842G>C (p.Arg281Pro) variant affecting the same Arg281 codon severely reduce the expression of downstream target genes [PMID: 33728612, 21163476]. Based on the available evidence, the c.841C>T (p.Arg281Cys) variant identified in the NR5A1 gene is reported as Pathogenic. |