Submissions for variant NM_000044.6(AR):c.1424C>T (p.Ala475Val)

gnomAD frequency: 0.00110  dbSNP: rs200390780

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000990851	SCV001141899	uncertain significance	Androgen resistance syndrome	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001356855	SCV002012680	uncertain significance	not provided	2019-09-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced activation associated with mildly affected AR function (Zuccarello et al., 2008); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in hemizygous state in published literature as A474V using alternate nomenclature, (Ferlin et al., 2006; Zuccarello et al., 2008) associated with male infertility.; This variant is associated with the following publications: (PMID: 28659371, 17970778, 23637914, 17054461, 27899157, 29723568, 28611373)
Genetic Services Laboratory, University of Chicago	RCV001702761	SCV002066126	likely benign	not specified	2019-05-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858727	SCV002220704	uncertain significance	Androgen resistance syndrome; Kennedy disease	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 475 of the AR protein (p.Ala475Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of mild androgen insensitivity syndrome, including idiopathic male infertility (PMID: 23637914, 27899157, 28611373, 28659371). This variant is also known as A474V. ClinVar contains an entry for this variant (Variation ID: 804019). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AR function (PMID: 17970778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001356855	SCV004165246	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	AR: BS1, BS2
Institute of Reproductive Genetics, University of Münster	RCV003983811	SCV004800810	uncertain significance	Male infertility	2024-01-16	criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356855	SCV001552127	likely benign	not provided		no assertion criteria provided	clinical testing	The AR p.Ala475Val variant was identified in the literature in 1 of 135 (freq: 0.007) males with Klinefelter Syndrome and in 2 of 292 Caucasian boys with isolated hypospadias but was not found in 345 controls (Valente_2017_PMID:28611373; Kalfa_2013_PMID:23637914). The variant was identified in dbSNP (ID: rs200390780) and ClinVar (classified as uncertain significance by Mendelics for Androgen resistance syndrome). The variant was identified in control databases in 113 of 82039 chromosomes (41 hemizygous) at a frequency of 0.001377 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: South Asian in 39 of 8024 chromosomes (freq: 0.00486), European (non-Finnish) in 64 of 34215 chromosomes (freq: 0.001871), Other in 2 of 2249 chromosomes (freq: 0.000889), African in 3 of 7372 chromosomes (freq: 0.000407), European (Finnish) in 3 of 11410 chromosomes (freq: 0.000263), Ashkenazi Jewish in 1 of 4294 chromosomes (freq: 0.000233) and Latino in 1 of 10673 chromosomes (freq: 0.000094), but was not observed in the East Asian population. The p.Ala475 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702761	SCV001927964	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702761	SCV001963939	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003918617	SCV004729194	benign	AR-related disorder	2022-04-14	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).