Submissions for variant NM_000044.6(AR):c.1823G>A (p.Arg608Gln)

dbSNP: rs137852573

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000382955	SCV000329075	likely pathogenic	not provided	2017-02-13	criteria provided, single submitter	clinical testing	The R608Q pathogenic variant has been reported numerous times in association with partial androgen insensitivity syndrome, including in two brothers who had clinical and endocrinological evidence of androgen resistance and developed breast cancer at the ages of 75 and 55 years (Wooster et al., 1992). R608Q was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R608Q variant is a semi-conservative amino acid substitution, that occurs at a position that is conserved across species. In silico analysis predicts this subsitution is probably damaging to the protein structure/function. Missense variants in nearby residues (T603P, I604N, D605Y, R609K, R609M, N611T) have been reported in the Human Gene Mutation Database in association with androgen insensitivity syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available evidence, we interpret R608Q as a pathogenic variant.
Invitae	RCV000806067	SCV000946047	pathogenic	Androgen resistance syndrome; Kennedy disease	2021-07-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9820). This variant has been observed in individual(s) with androgen insensitivity syndrome (PMID: 1303262, 9543136, 10221692, 11788616, 32985417). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 608 of the AR protein (p.Arg608Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Genetic Services Laboratory, University of Chicago	RCV000382955	SCV002067485	likely pathogenic	not provided	2020-06-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the AR gene demonstrated a sequence change, c.1823G>A, in exon 3 that results in an amino acid change, p.Arg608Gln. The p.Arg608Gln change affects a highly conserved amino acid residue located in a DNA binding domain of the AR protein that is known to be functional. The p.Arg608Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in the literature in other patients with both partial and complete androgen insensitivity and Reifenstein syndrome (PMIDs: 9039340, 9543136, 8723113, 1303262, 10221692). This sequence change absent from the large population databases such as ExAC and gnomAD (dbSNP rs137852573). The p.Arg608Gln amino acid change occurs in a region of the AR gene where other missense sequence changes have been described in patients with AR-related disorders. These collective evidences indicate that this sequence change is likely pathogenic.
OMIM	RCV000010494	SCV000030720	pathogenic	Partial androgen insensitivity syndrome	1998-04-01	no assertion criteria provided	literature only