ClinGen Dosage Sensitivity Curation Page

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  • 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 at exon 2 (18delC) predicted to cause a frameshift at the sixth codon for the aspartic acid and resultant termination at the 74th codon (D6fsX74). Absent in 100 control subjects. Western blot analysis indicated no evidence for the presence of such an amino-truncated 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 raised as a female with small dysgenetic testes, vasa deferentia, epididymides, absent uterus, blind-ending vagina, and clitoromegaly. Endocrine studies showed normal adrenal function and primary hypogonadism.
15472171 Mallett et al. (2004): Describes a heterozygous C16X mutation in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells. Per the authors, this mutation causes premature termination of translation and should abolish all SF1 activity.
21654157 Barbaro et al. (2011): describes a partial NR5A1 deletion affecting exons 2 and 3, leading to NR5A1 haploinsufficiency in a 46, XY patient presenting with female external genitalia with clitoromegaly, absence of a uterus, and mildly dysgenetic testes. The deletion was identified by MLPA.

Haploinsufficiency phenotype comments:

Heterozygous mutations in NR5A1 are traditionally associated with only gonadal dysgenesis. However, certain heterozygous mutations have also been reported in association with adrenocortical insufficiency (PMID: 11038323). Homozygous mutations of NR5A1 have been associated with adrenocortical insufficiency and gonadal dysgenesis. Six other reports describe nonsense or frameshift mutations consistent with sex reversal and/or adrenal insufficiency - PMID: 21691958, 20861607, 17694559, 19246354, 17488792, 22028768. See GeneReviews for clinical consequences in 46,XX individuals.

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