Submissions for variant NM_000044.6(AR):c.2323C>T (p.Arg775Cys)

dbSNP: rs137852562

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001056795	SCV001221259	pathogenic	Androgen resistance syndrome; Kennedy disease	2021-10-27	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 9804). 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"). Experimental studies have shown that this missense change affects AR function (PMID: 1609793, 2082179). This variant disrupts the p.Arg775 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1609793, 10690872, 22334387, 24737579). 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. This variant is also known as R774C, Arg774Cys, and Arg773Cys. This sequence change replaces arginine, a(n) basic and polar amino acid, with cysteine, a(n) neutral and slightly polar amino acid, at codon 775 of the AR protein (p.Arg775Cys). 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: 1609793, 2082179, 8990010, 9627582, 12705360, 20150575, 28624954). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals.
Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology	RCV000010478	SCV001960999	pathogenic	Androgen resistance syndrome		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818149	SCV002065909	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the AR gene demonstrated a sequence change, c.2323C>T, in exon 6 that results in an amino acid change, p.Arg775Cys. The p.Arg775Cys change affects a highly conserved amino acid residue located in a domain of the AR protein that is known to be functional. The p.Arg775Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in multiple individuals and families with AR-related disorders (PMID: 1609793, 9627582, 1856263, 8990010, 9544375, 2082179, 28624954, 20150575, 12705360). This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Arg775Cys amino acid change occurs in a region of the AR gene where several other missense sequence changes have been described in individuals with AR-related disorders. Additionally, a different missense change at the same amino acid residue has been identified in individuals with AR-related disorders (PMID: 15925895, 1307250, 10690872, 1609793, 22334387, 247375790). Based on these collective evidences, this sequence change is classified as pathogenic.
OMIM	RCV000010478	SCV000030704	pathogenic	Androgen resistance syndrome	2013-10-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000010478	SCV000692162	pathogenic	Androgen resistance syndrome	2013-07-12	no assertion criteria provided	clinical testing