ClinVar Genomic variation as it relates to human health

This variant has been identified by standard clinical testing.

Variant summary: AR c.2612C>T (p.Ala871Val) results in a non-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 1.1e-05 in 181154 control chromosomes (i.e, 2 heterozygous female carriers; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2612C>T has been reported in the literature in multiple hemizygous males affected with Androgen Resistance Syndrome (e.g., Hiort_1994, Hiort_1996, Bhangoo_2010, Zhang_2019, Kumar_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20305676, 8723113, 8033918, 34689141, 31219235). Four ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Criteria applied: PS4,PM5_STR,PM1,PM2_SUP,PP3,PP4

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with androgen insensitivity (MIM#300068), androgen insensitivity, partial, with or without breast cancer (MIM#312300), hypospadias 1, X-linked (MIM#300633), or spinal and bulbar muscular atrophy of Kennedy (MIM#313200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ligand-binding domain of nuclear hormone receptor (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been reported in several individuals with 46,XY differences of sex development in the literature (PMIDs: 8033918, 28261839, 34689141, 27051040). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

DNA sequence analysis of the AR gene demonstrated a sequence change, c.2612C>T, in exon 8 that results in an amino acid change, p.Ala871Val. The p.Ala871Val change affects a moderately conserved amino acid residue located in the ligand binding domain of the AR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala871Val substitution. This sequence change has been described in the gnomAD database in the heterozygous state in two individuals which corresponds to a population frequency of 0.0011% (dbSNP rs143040492). This pathogenic sequence change has previously been described in multiple individuals with AR-related disorders (PMID: 31219235, 8033918, 28261839, 20305676, 8723113). Additionally, other variants impacting this same amino acid residue, p.Ala871Gly and p.Ala871Glu, have been reported in individuals with AR-related disorders (PMID: 7981687, 9332480). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 871 of the AR protein (p.Ala871Val). 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 individuals with androgen insensitivity syndrome (PMID: 8033918, 8723113, 20305676, 28261839). This variant is also known as p.Ala870Val. ClinVar contains an entry for this variant (Variation ID: 492801). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ala871 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (PMID: 7981687, 8723113, 9332480), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.