ClinVar Miner

Submissions for variant NM_000044.6(AR):c.2668G>A (p.Val890Met) (rs886041133)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000280545 SCV000329082 pathogenic not provided 2015-08-12 criteria provided, single submitter clinical testing The V890M pathogenic variant in the AR gene has been reported previously as V889M in association with both complete and partial androgen insensitivity syndrome (de Bellis et al., 1994; Ahmed et al., 2000; Audi et al., 2010). This variant alters a residue in the highly conserved ligand binding domain of the protein, and functional studies indicate that it impairs androgen binding capacity (de Bellis et al., 1994). V890M was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V890M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V890M as a pathogenic variant.
Invitae RCV000696602 SCV000825168 pathogenic Androgen resistance syndrome; Bulbo-spinal atrophy X-linked 2018-04-24 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 890 of the AR protein (p.Val890Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with complete androgen insensitivity syndrome (PMID: 10690872, 14974091, 15925895, 24737579, 20150575). The variant is also known as p.Val889Met and p.Val888Met in the literature. ClinVar contains an entry for this variant (Variation ID: 279690). Experimental studies have shown that this missense change has a higher ligand dissociation rate, and the mutant protein is unstable. This mutant receptor also fails to transactivate a reporter gene at low levels of androgen (PMID: 8126121). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582566 SCV000692176 pathogenic Androgen resistance syndrome 2016-11-15 no assertion criteria provided clinical testing

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