ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.