ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15579739 Hasegawa et al. (2004) describes a heterozygous single base pair deletion in exon 2 (18delC) of the NR5A1 gene predicted to cause a frameshift at the sixth codon for the aspartic acid amino acid and resultant termination at the 74th codon (D6fsX74). The variant was absent in 100 control subjects consented for this study. Western blot analysis indicated no evidence for the presence of the SF-1 protein; transcription analysis using the human CYP11A promoter indicated that the mutation was transcriptionally inactive and had no dominant negative effect. The proband was a 27 year old 46,XY individual born to non-consanguineous parents who was raised as a female presenting with small dysgenetic testes, vasa deferentia, epididymides, absent uterus, blind-ending vagina, and clitoromegaly. Endocrine studies showed normal adrenal function and primary hypogonadism. No sequence variants were detected in SRY, LHX9, or DMRT1. Proband had two older brothers who were clinically normal. Parents of the proband declined molecular testing.
15472171 Mallett et al. (2004) describes a heterozygous C16X variant in the NR5A1 gene in a 46,XY patient born to non-consanguineous parents showing gonadal dysgenesis with normal adrenal function with low levels of anti-m?llerian hormone and testosterone, weak testosterone response to hCG, and hypoplastic testes with abundant seminiferous tubules but rare germ cells. Per the authors, this mutation causes premature termination of translation and should abolish all SF-1 activity. Molecular sequencing of the parents demonstrated that this variant occurred de novo in the proband.
21654157 Barbaro et al. (2011) describes a partial NR5A1 deletion affecting exons 2 and 3, leading to NR5A1 haploinsufficiency in a 46,XY proband born to consanguineous parents who presented with female external genitalia with clitoromegaly, absence of a uterus, mildly dysgenetic testes, and elevated testosterone and follicle-stimulating hormone levels. The deletion was identified by MLPA. Parents were not tested therefor it is unclear if this partial deletion was inherited or de novo.
22028768 Allali et al. (2011) describes a heterozygous four base pair insertion at nucleotide position 140 of the NR5A1 gene located within the zinc finger domain (c.140_141insCACG). This frameshift variant is predicted to alter the protein coding sequence and create a premature termination codon at codon 87. It is predicted to undergo nonsense-mediated decay. The analysis of the father showed a normal NR5A1 sequence while the mother was unavailable for study. The sequence of the SRY gene was normal. The proband (Patient 4, Table 1) was first evaluated as a 1 day old 46,XY with ambiguous external genitalia without uterus. At 4 months the proband?s testosterone and luteinizing hormone were below expected limits while inhibin B and anti-m?llerian hormone were within limits for age.
17488792 Coutant et al. (2007) describes a heterozygous single base pair deletion at nucleotide position 536 of the NR5A1 gene (c.536delC) which replaces the proline at position 179 with a histidine, causes a frameshift, and prematurely terminates at position 295, 116 codons after the codon encoding for proline at codon 179 (p.P179HfsX116). Per the authors, this mutation should produce a protein with normal DNA-binding domain (DBD) and A box but lacking the normal C-terminal half of the hinge region, the ligand-binding domain (LBD) and the activation function 2 (AF-2) domain. This variant was observed in two siblings with a 46,XY karyotype and mother. The index case had ambiguous genitalia, perineal urogenital sinus, palpable gonads in bilateral inguinal regions, hypotrophic scrotum or corrugation of major labia, normal levels of testosterone, inhibin B, follicle stimulating hormone, anti-m?llerian hormone, and luteinizing hormone were observed from birth up to 4 months. No uterus was seen on pelvic ultrasound and genitography revealed a vaginal pouch. Histology of the gonad showed normal infantile testicular structure; seminiferous tubules lined with Sertoli cells contained some spermatogonia, and interstitium showed small clusters of Leydig cells. The second 46,XY sibling shown a small genital tubercle and no uterus via 20 wk gestation ultrasound. At birth, external genitalia were less virilized than in the older sibling, with a perineal urogenital sinus, small palpable gonads in the bilateral inguinal regions, and corrugation of major labia. Testosterone, anti-m?llerian hormone, and inhibin B levels were consistently low from birth up to 45 days. However, luteinizing hormone and follicle stimulating hormone levels during the first weeks of life were inappropriately low in view of the hypogonadism, which suggested a defect in gonadotrope function. No uterus was seen on pelvic ultrasound, and genitography revealed a vaginal pouch. The mother presented at 30 years with normal genitalia and sufficient fertility.

Haploinsufficiency phenotype comments:

Additional evidence includes: PMID 23918653 Harrison et al. (2013) describes a heterozygous 0.232 Mb microdeletion on 9p33.3 [chr9:127,251,113?127,487,356 (GRChr37/hg19] which includes NR5A1, NR6A1, MIR181A2HG, MIR181A2, and MIR181B2. This deletion was observed in 46,XY proband who initially presented at 15 days of life with ambiguous genitalia, with clitoromegaly, a urogenital sinus, and bilateral labioscrotal masses with a neonatal female testosterone level, normal adrenal steroidogenic function, no internal M?llerian structures and bilateral labioscrotal testes. At 6 months age, bilateral testicular biopsies demonstrated closely packed seminiferous tubules mostly containing germ cells. Some of the germ cells were bi- or tri-nucleated and located more centrally within the tubules. Neither Leydig cells nor M?llerian structures were observed, consistent with partial gonadal dysgenesis. The proband?s mother was also positive for the microdeletion and had developed secondary amenorrhea at age 28 which was unresponsive to multiple hormonal therapies. She had normal genitalia, vagina, cervix and uterus with postmenopausal hormonal values. Computed tomography revealed normal adrenal glands, moderate hepatomegaly and diverticulosis of the sigmoid colon. PMID 25497574 Baetens et al. describes a heterozygous p.Y211Pfs*12 variant in the NR5A1 gene. This variant was observed in a 46,XY individual with atypical genitalia. RT-qPCR in the patient?s lymphoblasts showed a lower expression of NR5A1 mRNA. Segregation analysis indicated that this mutation was present in (1) the asymptomatic patient?s mother, (2) maternal aunt, who had been diagnosed with primary ovarian insufficiency at the age of 35, and (3) grandfather, who had been operated for proximal hypospadias, but spontaneously fathered two children. PMID 28033660 Domenice et al. (2016) describes five unrelated 46,XY probands with atypical external genitalia and frameshift variants in the NR5A1 gene (p.Cys246X, patient 2; p.Tyr211X, patient 5; p.Glu295del, patient 6; p.Tyr404X, patient 10, and p.Cys412X, patient 11). The mother of patient 5 also carries the p.Tyr211X variant and developed primary ovarian insufficiency at 39 years. PMID 28459839 Werner et al. (2017) describes a heterozygous p.Y211Tfs*83 variant in the NR5A1 gene. This variant was observed in a 46,XY proband with complete gonadal dysgenesis, their 46,XY sibling with partial gonadal dysgenesis and primary amenorrhea at 14 years of age, 46,XX female presenting sibling, and mother. Transcription analysis using the human AMH and STAR promoters indicated that the mutation was transcriptionally inactive with levels below 10% and 5%, respectively. The phenotype of the 46,XX sibling and mother were not discussed. PMID 31513305 Fabbri-Scallet et al. (2019) describes in their review 60 NR5A1 frameshift or nonsense variants that were observed in 46,XY individuals with complete gonadal dysgenesis (characterized by female internal and external genitalia and streak gonads), partial gonadal dysgenesis (characterized by ambiguous genitalia and dysgenic testes with or without contralateral streak gonad), and those presenting with ambiguous genitalia, normal testosterone production, and absence of AR and SRD5A2 variants. Haploinsufficiency score was determined based on evidence from patients with a 46,XY karyotype and NR5A1 loss of function presenting with internal and/or external ambiguous genital or female genital. However, evidence suggests that individuals with a 46,XX karyotype and NR5A1 loss of function can present with primary ovarian insufficiency (see PMID: 19246354, 23918653, 25497574, 28033660)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity