ClinVar Miner

Submissions for variant NM_000044.6(AR):c.1847G>A (p.Arg616His)

gnomAD frequency: 0.00001  dbSNP: rs754201976
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000288478 SCV000329076 pathogenic not provided 2021-11-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on androgen-responsive elements, decreasedDNA binding and transactivation ability (Mowszowicz et al., 1993; Beitel et al., 1994); Not observed at a significant frequency 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: 8413310, 8162033, 8339746, 15531547, 25613104, 17054461, 11549642, 9627582, 29051026, 8723113, 24186138, 11181525, 9698822, 31012339, 32985417)
Invitae RCV000532795 SCV000629586 pathogenic Androgen resistance syndrome; Kennedy disease 2022-03-10 criteria provided, single submitter clinical testing This variant is also known as R614H, R615H, and R606H. This missense change has been observed in individuals with complete androgen insensitivity syndrome (CAIS) (PMID: 8162033, 8413310, 8723113, 9698822, 11549642, 15531547, 24186138, 25613104). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs754201976, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 616 of the AR protein (p.Arg616His). ClinVar contains an entry for this variant (Variation ID: 279684). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 8162033, 8413310, 11181525). 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").
Clinical Genetics and Genomics, Karolinska University Hospital RCV000288478 SCV001450199 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing

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