Submissions for variant NM_000044.6(AR):c.1174C>T (p.Pro392Ser)

gnomAD frequency: 0.00163  dbSNP: rs201934623

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499525	SCV000593280	benign	not specified	2016-09-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000990850	SCV001141898	benign	Androgen resistance syndrome	2024-02-28	criteria provided, single submitter	clinical testing
Invitae	RCV001516905	SCV001725277	benign	Androgen resistance syndrome; Kennedy disease	2024-01-31	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV002221510	SCV002098054	benign	Androgen resistance syndrome; Partial androgen insensitivity syndrome	2022-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001269900	SCV004165241	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	AR: PP3, BS1, BS2
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000990850	SCV004190290	likely benign	Androgen resistance syndrome	2023-11-20	criteria provided, single submitter	clinical testing	ACMG:PM1 PP3 BS1 BP2 BP4
PreventionGenetics, part of Exact Sciences	RCV003927863	SCV004738456	likely benign	AR-related disorder	2023-07-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000990850	SCV004809909	uncertain significance	Androgen resistance syndrome	2024-04-04	criteria provided, single submitter	clinical testing
UCLA Clinical Genomics Center, UCLA	RCV000196772	SCV000255325	pathogenic	Partial androgen insensitivity syndrome	2014-07-01	flagged submission	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000627669	SCV000746022	uncertain significance	Hypospadias 1, X-linked	2018-01-31	no assertion criteria provided	clinical testing	The observed variant c.1174C>T (p.P392S) has the minor allele frequency of 0.74% in 1000 Genomes and 0.8% in ExAC databases. The in silico predictions of the variant is polymorphism by Mutation Taster, benign by PolyPhen and damaging by SIFT.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269900	SCV001450250	pathogenic	not provided	2014-08-20	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269900	SCV001549096	likely benign	not provided		no assertion criteria provided	clinical testing	The AR p.Pro392Ser variant was identified in 4 of 584 proband chromosomes (frequency: 0.00685) from a Caucasian population presenting with isolated hypospadias without micropenis or cryptorchidism, and was not identified in 690 control chromosomes from healthy individuals (Kalfa_2013_23637914). The variant was also identified in dbSNP (ID: rs201934623) as "With Pathogenic allele" and ClinVar (3 submissions with conflicting interpretations of pathogenicity: Benign(1) by Genetic Services Laboratory, University of Chicago (2016); Pathogenic(1) by UCLA Clinical Genomics Center, UCLA - CES (2014); and Uncertain significance(1) by Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics (2018)). Submitters report the variant to be linked to Partial Androgen Insensitivity syndrome and Hypospadias 1, X-linked. The variant was also identified in Clinvitae, Cosmic, MutDB, and LOVD 3.0 (likely benign). The variant was identified in control databases in 684 of 166808 chromosomes (4 homozygous) at a frequency of 0.004101 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 404 of 16297 chromosomes (freq: 0.02479), Other in 16 of 4579 chromosomes (freq: 0.003494), Ashkenazi Jewish in 22 of 6922 chromosomes (freq: 0.003178), European (non-Finnish) in 189 of 71137 chromosomes (freq: 0.002657), Latino in 46 of 25450 chromosomes (freq: 0.001807), African in 5 of 14750 chromosomes (freq: 0.000339), East Asian in 1 of 12487 chromosomes (freq: 0.00008), and European (Finnish) in 1 of 15186 chromosomes (freq: 0.000066). Chakrabarty et al. identified the variant p.Pro392Ser as a somatic driver mutation in tissue samples of 18 long-standing ulcerative colitis (UC) subjects at high risk of colorectal carcinoma. (Chakrabarty_2017_28524162). The p.Pro392Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Chakrabarty, Sanjiban, et al. "Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia." British journal of cancer 117.1 (2017): 136. Kalfa, Nicolas, et al. "Minor hypospadias: the “tip of the iceberg” of the partial androgen insensitivity syndrome." PloS one 8.4 (2013): e61824.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001269900	SCV001799543	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001269900	SCV001972056	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001269900	SCV001978058	likely benign	not provided		no assertion criteria provided	clinical testing