Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000814875 | SCV000955308 | pathogenic | Androgen resistance syndrome; Kennedy disease | 2023-07-04 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects AR function (PMID: 1430233, 8040309). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg941 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430233, 8040309, 8824883, 11788673, 15925895, 20011049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. ClinVar contains an entry for this variant (Variation ID: 9829). This variant is also known as p.R838H, p.R839H, and p.R840H. This missense change has been observed in individuals with androgen insensitivity syndome (PMID: 1430233, 8040309, 16450583, 25241384, 27267075, 28186600, 28624954). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 841 of the AR protein (p.Arg841His). |
Clinical Genetics and Genomics, |
RCV001269861 | SCV001450175 | pathogenic | not provided | 2016-01-21 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001269861 | SCV001768156 | pathogenic | not provided | 2019-09-10 | criteria provided, single submitter | clinical testing | Observed in several unrelated patients with androgen insensitivity syndrome in published literature (McPhaul et al., 1992; Beitel et al., 1994); Published functional studies demonstrate a damaging effect on GH gene promotion as well as ligand binding (Beitel et al., 1994); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32985417, 3605226, 8040309, 28624954, 1430233, 28186600, 25241384, 16450583, 15835798, 27267075) |
3billion | RCV000582333 | SCV004013543 | pathogenic | Androgen resistance syndrome | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009829 / PMID: 1430233). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 1430233, 16450583, 25241384, 28624954, 32985417). Different missense changes at the same codon (p.Arg841Cys, p.Arg841Gly, p.Arg841Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009830 / PMID: 10502786, 1430233, 9856504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. | |
OMIM | RCV000010503 | SCV000030729 | pathogenic | Partial androgen insensitivity syndrome | 1994-08-01 | no assertion criteria provided | literature only | |
Clinical Molecular Genetics Laboratory, |
RCV000582333 | SCV000692167 | pathogenic | Androgen resistance syndrome | 2007-11-30 | no assertion criteria provided | clinical testing |