Submissions for variant NM_003140.3(SRY):c.196G>C (p.Ala66Pro)

dbSNP: rs2124486291

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001533005	SCV001745385	likely pathogenic	46,XY disorder of sex development	2021-07-06	criteria provided, single submitter	clinical testing	A hemizygous, likely pathogenic variant was identified in the SRY gene (NM_003140.2:c.196G>C, p.Ala66Pro). This variant has not been observed in large population databases (Genome Aggregation Database v2.1.1). A different missense change at the same codon (c.196G>A, p.Ala66Thr) has previously been reported as pathogenic in a phenotypic female with a 46,XY karyotype and complete gonadal dysgenesis. The p.Ala66Pro variant substitutes the alanine with proline at position 66 of the protein. This highly conserved residue is located in the high mobility group (HMG) box domains that is responsible for binding DNA, and may be involved in protein-protein interactions (UniProt Q05066). Experimental studies have shown that several pathogenic missense variants in this region reduce the binding capacity of SRY to DNA sequences. There is also evidence that missense changes in this region impair nuclear localization. There is consensus among in silico tools that the p.Ala66Pro change is damaging to protein function, but these predictions have not been confirmed by functional studies. Based on ACMG guidelines, this variant is classified as likely pathogenic.