Submissions for variant NM_000044.6(AR):c.2086G>A (p.Asp696Asn)

dbSNP: rs1555995840

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001853948	SCV002246671	pathogenic	Androgen resistance syndrome; Kennedy disease	2022-12-10	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects AR function (PMID: 1775137). Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 492787). This variant is also known as Asp686Asn. This missense change has been observed in individual(s) with complete androgen insensitivity syndrome (PMID: 1775137, 31499074). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 696 of the AR protein (p.Asp696Asn). This variant disrupts the p.Asp696 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (PMID: 1775137, 9554754), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003236821	SCV003935805	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on ligand-binding affinity and transcriptional activity (Ris-Stalpers et al., 1991) Ris-Stalpers C et al. (1991) Mol Endocrinol 5 (10):1562-9 (PMID: 1775137); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27899157, 31499074, 17054461, 9627582, 15531547, 18710728, 20150575, 30496128, 22334387, 1775137)
Baylor Genetics	RCV000581269	SCV004040995	pathogenic	Androgen resistance syndrome	2023-08-05	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581269	SCV000692152	pathogenic	Androgen resistance syndrome	2010-03-10	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000581269	SCV002754546	likely pathogenic	Androgen resistance syndrome	2022-09-15	no assertion criteria provided	clinical testing