Submissions for variant NM_000044.6(AR):c.2395C>G (p.Gln799Glu)

gnomAD frequency: 0.00137  dbSNP: rs137852591

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224621	SCV000281524	likely pathogenic	not provided	2015-02-02	criteria provided, single submitter	clinical testing
Invitae	RCV001519068	SCV001727873	benign	Androgen resistance syndrome; Kennedy disease	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV002247311	SCV002518509	pathogenic	Malignant tumor of prostate	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234899	SCV003934341	uncertain significance	not specified	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: AR c.2395C>G (p.Gln799Glu) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 183191 control chromosomes to include both hemizygous males and heterozygous females. This frequency does not allow conclusions about variant significance, although pointing to a benign outcome. c.2395C>G has been reported in the literature in settings of females with partial androgen insensitivity (example, Batch_1992), in combination with a different AR gene variant p.Cys807Phe in a female with complete androgen insensitivity (example, Petroli_2017) and in other settings such as azoospermic/infertile males (example, Wang_1998, Hiort_2000). These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function (example, Wang_1998, Petroli_2017). The most pronounced variant effect results in normal ability to bind androgen receptor (Wang_1998, Petroli_2017) and conflicting results in transactivation activity ranging from a slight reduction to normal levels (Wang_1998, Petroli_2017). Furthermore, a recent report has identified that a complex allele combination of this variant with p.Cys807Phe results in a deleterious outcome thereby questioning the role of this variant in isolation in the associated pathophysiology of disease (Petroli_2017). The following publications have been ascertained in the context of this evaluation (PMID: 1307250, 10946887, 29237170, 9921903). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000224621	SCV004165249	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	AR: BS2
Institute of Reproductive Genetics, University of Münster	RCV003982835	SCV004800820	uncertain significance	Male infertility	2024-01-16	criteria provided, single submitter	research
OMIM	RCV000010520	SCV000030746	pathogenic	Partial androgen insensitivity syndrome	1998-12-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224621	SCV001553226	uncertain significance	not provided		no assertion criteria provided	clinical testing	The AR p.Q799E variant was identified in the literature in multiple patients with androgen insensitivity syndrome (AIS), including the complete, partial and mild forms (Batch_1992_PMID:1307250; Petroli_2017_PMID:29237170; Jääskeläinen_2006_PMID:16595706; Hughes_2012_PMID:23044881). The p.Q799E variant was also identified in a male azoospermic patient and a male with prostate cancer (Wang_1998_PMID:9851768; Evans_1996_PMID:8628719). The variant was identified in dbSNP (ID: rs137852591), LOVD 3.0, Cosmic and ClinVar (classified as likely pathogenic by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was also found in the Cambridge AR Mutation Database in association with mild AIS and partial AIS (Hughes_2012_PMID:23044881). The variant was identified in control databases in 305 of 204870 chromosomes (104 hemizygous) at a frequency of 0.001489 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 51 of 18607 chromosomes (freq: 0.002741), European (non-Finnish) in 229 of 92423 chromosomes (freq: 0.002478), Ashkenazi Jewish in 11 of 7652 chromosomes (freq: 0.001438), Other in 6 of 5319 chromosomes (freq: 0.001128), Latino in 6 of 28040 chromosomes (freq: 0.000214), African in 1 of 18937 chromosomes (freq: 0.000053) and South Asian in 1 of 19071 chromosomes (freq: 0.000052), but was not observed in the East Asian population. The p.Q799E variant was identiifed in combination with a p.C807F variant in a female with complete AIS; functional studies of these variant indicated that the p.Q799E variant was not harmful on its own but had a synergistic negative effect when found as a double mutant with the p.C807F variant (Petroli_2017_PMID:29237170). Petroli et al. (2017) also identified the p.Q799E variant as a double mutant with p.F726V in another patient with AIS, suggesting that the p.Q799E variant may modulate or contribute to the AIS phenotype. Despite being found in the ligand binding domain, multiple functional studies have not found any ligand binding defects from this variant, and the effect of this variant on receptor trans-activation function has been minimal or insignificant compared to wildtype (Wang_1998_PMID:9851768; Bevan_1995_PMID:8824883; Jääskeläinen_2006_PMID:16595706). The p.Gln799 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is classified as a variant of uncertain significance, although this variant may contribute to AIS when found in combination with other AR variants.