ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000024.9) (NC_000024.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
1639410 McElreavey et al. (1992) identified a de novo C-to-T transition at nucleotide 687 in the SRY gene in an XY sex-reversed female with pure gonadal dysgenesis. This mutation changed a glutamine codon (CAG) to a termination codon (TAG) in the putative DNA-binding motif.
1339396 Hawkins et al. (1992) identified 3 patients with alterations in SRY and XY sex reversal. This first was a de novo 1-basepair deletion (734A) of the SRY gene in a patient with complete gonadal dysgenesis and a 46,XY karyotype. This variant causes a frameshift. The remaining two were point mutations. All three variants caused alterations in the putative DNA-binding region of the SRY protein.
7987333 Iida et al. (1994) identified a G-to-A transition in the SRY gene in an XY sex-reversed female. This mutation changed a tryptophan codon to a termination codon (W107X). Inheritance not reported

Haploinsufficiency phenotype comments:

Additional studies Earlier accounts by Jager et al. (1990; PubMed: 2247151) showed 1 patient out of the 12 XY sex-reversed females with a de novo 4-bp deletion in a conserved DNA-binding motif. Cameron and Sinclair (1997; PubMed: 9143916) provided 5 case reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. Among 4 individuals, the father carried the same SRY mutation as his 46,XY daughter. Sharp et al. (2005) studied causes of incomplete masculinization in 15 individuals, where a segment of Yp was translocated onto Xp. Among 5 of 6 translocation carriers, breakpoints were close to SRY, or disrupted expression of genes near SRY, suggesting alteration of normal SRY expression by position effects rather than X inactivation. It was also noted through expression studies that there is little evidence for spreading of X inactivation into Yp chromatin. Assump?o et al (2005; PMID: 16218050) described a SRY promoter (e.g. three base pair deletion in Sp1 binding sites). This was shown in one patient with complete XY gonadal dysgenesis. This deletion in the promoter was also found in the father and several relatives referred to have sexual ambiguity. -------------------------------------------------------------------- More recent literature continues to describe loss of function mutations in SRY leading to 46,XY complete gonadal dysgenesis (CGD) and supports role for haploinsufficiency. one patient with CGD phenotype and 46,XY female described in PMID: 31446095; 2019 ? c.161delG frameshift , inheritance unknown (9 other studies described in Table 5) additional patient with CGD phenotype and 46,XY female described in PMID: 31361042; 2019 missense mutation c.266 A>T ? inheritance unknown , family members did not want to participate in additional testing additional patients with CGD phenotype and 46,XY female described in PMID: 29378242; 2018 PMID: 22288726 with a novel missense variant Ala66Thr, not inherited from the father. patient with CGD phenotype also described in has a missense variant in the HMG domain of SRY, p.Arg130Pro, c.389G>C) ? see Fig 2 Many other pathogenic loss of function variants described in ClinVar, some in the HMG box domain of SRY. Mutations in the HMG box of the SRY gene are found in approximately 10?15% of 46,XY pure gonadal dysgenesis cases that highlight the important role of SRY gene in testis development or differentiation. The HMG domain of SRY plays a key role in its DNA binding activity (PMID: 15687343). In terms of inheritance, variants described outside of the HMG domain may be inherited with no overt phenotype in the transmitting father, however this correlation is not rigorous and does not exclude alternative regulatory mechanisms, such as SRY-directed RNA splicing ( familial frameshift SRY variant was shown to be inherited from a mosaic father with testicular dysgenesis sdyndrome but normal fertility (described here PMID: 22288726, 19531589 ). Some of these do occur in the HMG domain but in mosaic context in the father (PMID: 20849656) Taken together, the SRY gene is believed to be critical in initiating male sex determination by triggering undifferentiated gonadal tissue to transform into testes. Loss of function variants in SRY cause 46,XY sex reversal. These alterations in SRY account for 15-20% of SRY-related Sawyer syndrome in which phenotypic females with 46,XY chromosomal constitution have functional female genitalia but lack ovaries.

The ratings for loss-of-function and triplosensitivity for genes on the Y chromosome are made in the same fashion as for genes linked to autosomal dominant disorders.

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

Triplosensitivity phenotype comment:

There is no substantial evidence for focal duplications, involving only SRY leading to a phenotype. No duplications involving only SRY described in DECIPHER (public version; accessed 12/2020) or ClinVar CNVs (accessed, 12/2020) Premi et al (PMID: 16510537) described tandem duplications of SRY among individuals with sex chromosome related anomalies as well as natural background radiation. Copy number changes in SRY detected by RT-PCR ranged from 2-16 copies (Table 1, 16 patients). No genotype-phenotype correlation was provided. Although 47,XXY, 46,XX males with a gain of SRY on the X due to an aberrant translocation, or isodicentric Yp with extra copy SRY have been reported in well-known phenotypes; they are not considered in this instance as these occur usually in the background of other genes involved in the structural rearrangement or whole chromosome gain

The ratings for loss-of-function and triplosensitivity for genes on the Y chromosome are made in the same fashion as for genes linked to autosomal dominant disorders.