Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000280545 | SCV000329082 | pathogenic | not provided | 2023-06-21 | criteria provided, single submitter | clinical testing | Published functional studies found this variant is associated with significant impairment of androgen binding capacity (de Bellis et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Missense variants in this gene are often considered pathogenic (HGMD); Also known as p.(V889M); This variant is associated with the following publications: (PMID: 29785970, 26522496, 14974091, 27802905, 10690872, 10425033, 20150575, 15925895, 27051040, 27022412, 33516834, 24737579, 8126121) |
Invitae | RCV000696602 | SCV000825168 | pathogenic | Androgen resistance syndrome; Kennedy disease | 2022-02-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 890 of the AR protein (p.Val890Met). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 8126121). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 279690). This variant is also known as p.Val889Met and p.Val888Met. This missense change has been observed in individuals with complete androgen insensitivity syndrome (PMID: 10690872, 14974091, 15925895, 20150575, 24737579). This variant is present in population databases (no rsID available, gnomAD 0.008%). |
Victorian Clinical Genetics Services, |
RCV000582566 | SCV002767555 | pathogenic | Androgen resistance syndrome | 2020-06-11 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, however the androgen insensitivity (AIS) phenotype is known to only be caused by variants resulting in a loss-of-function (OMIM, PMID: 22334387). (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Minor amino acid change, very high conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternate change to leucine at the same residue has previously been reported as pathogenic in at least two patients with AIS (ClinVar, HGMD, PMID: 20150575). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with both complete and partial AIS (ClinVar, HGMD, PMID: 10425033, PMID: 24737579, PMID: 27051040). (P) 0903 - Low evidence for segregation with disease. The variant has previously been shown to segregate with AIS in at least one family (PMID: 29785970). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies of the variant in transfected cells demonstrated reduced androgen binding capacity (PMID: 8126121). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
3billion | RCV000582566 | SCV004013453 | pathogenic | Androgen resistance syndrome | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 8126121). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279690 / PMID: 10425033). A different missense change at the same codon (p.Val890Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430163, VCV001338633 / PMID: 20150575). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. | |
Clinical Molecular Genetics Laboratory, |
RCV000582566 | SCV000692176 | pathogenic | Androgen resistance syndrome | 2016-11-15 | no assertion criteria provided | clinical testing |