Submissions for variant NM_000044.6(AR):c.2667C>T (p.Ser889=)

dbSNP: rs137852594

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001059742	SCV001224386	pathogenic	Androgen resistance syndrome; Kennedy disease	2021-04-02	criteria provided, single submitter	clinical testing	This variant has been reported to disrupt splicing of the AR mRNA and result in a non-functional Androgen Receptor (PMID:11397856). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals with partial androgen insensitivity syndrome (PMID: 11397856, 20150575, 1158706). ClinVar contains an entry for this variant (Variation ID: 9850). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 889 of the AR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the AR protein.
GeneDx	RCV001785450	SCV002568557	pathogenic	not provided	2022-08-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate activation of a cryptic splice donor site and subsequent alternative splicing (Hellwinkel et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Also known as S888S; This variant is associated with the following publications: (PMID: 11587068, 11397856, 33505695, 20150575)
Illumina Laboratory Services, Illumina	RCV001785450	SCV003802771	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	The AR c.2667C>T (p.Ser889=) synonymous variant results in the substitution of cytosine at nucleotide position 2667 with thymine. Across a selection of the available literature, the c.2667C>T variant has been identified in a hemizygous state in at least four individuals with androgen insensitivity syndrome, characterized by atypical genitalia, hypospadias, low levels of luteinizing and follicle stimulating hormone, and cryptorchidism (PMID: 11397856, 28743543, 33505695, 35561789). The variant segregated in three affected males and unaffected carrier mothers in a multi-generational family (PMID: 35561789). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrated that the c.2667C>T variant produces an aberrant splicing variant that leads to partial skipping of exon 8 and a shortened 3'-untranslated region and the androgen-induced transcriptional activity is inhibited (PMID: 11397856). Based on the available evidence, the c.2667C>T (p.Ser889=) variant is classified as pathogenic for androgen insensitivity syndrome.
OMIM	RCV000010524	SCV000030750	pathogenic	Androgen resistance syndrome	2001-06-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000010524	SCV000692140	pathogenic	Androgen resistance syndrome	2001-11-27	no assertion criteria provided	clinical testing