Submissions for variant NM_000044.6(AR):c.1846C>T (p.Arg616Cys)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499725	SCV000593283	pathogenic	Androgen resistance syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000499725	SCV000891627	pathogenic	Androgen resistance syndrome	2017-12-30	criteria provided, single submitter	curation
3billion	RCV000499725	SCV002573129	likely pathogenic	Androgen resistance syndrome	2022-09-01	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: 0.98; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000434266). A different missense change at the same codon (p.Arg616His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279684). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222977	SCV005863914	pathogenic	Androgen resistance syndrome; Kennedy disease	2024-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 616 of the AR protein (p.Arg616Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with complete androgen insensitivity syndrome (PMID: 22334387, 24229697). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 434266). Invitae Evidence 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 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. This variant disrupts the p.Arg616 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8162033, 8413310, 8723113, 9698822, 11549642, 15531547, 24186138, 25613104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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