chrX-67686064-G-A

Position:

• chrX-67686064-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000044.6(AR):​c.1823G>A​(p.Arg608Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.02

Genes affected

AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a zinc_finger_region NR C4-type (size 24) in uniprot entity ANDR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• PP5: Variant X-67686064-G-A is Pathogenic according to our data. Variant chrX-67686064-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67686064-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.1823G>A	p.Arg608Gln	missense_variant	3/8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1823G>A	p.Arg608Gln	missense_variant	3/8	1	NM_000044.6	ENSP00000363822	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 03, 2020	DNA sequence analysis of the AR gene demonstrated a sequence change, c.1823G>A, in exon 3 that results in an amino acid change, p.Arg608Gln. The p.Arg608Gln change affects a highly conserved amino acid residue located in a DNA binding domain of the AR protein that is known to be functional. The p.Arg608Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in the literature in other patients with both partial and complete androgen insensitivity and Reifenstein syndrome (PMIDs: 9039340, 9543136, 8723113, 1303262, 10221692). This sequence change absent from the large population databases such as ExAC and gnomAD (dbSNP rs137852573). The p.Arg608Gln amino acid change occurs in a region of the AR gene where other missense sequence changes have been described in patients with AR-related disorders. These collective evidences indicate that this sequence change is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2017	The R608Q pathogenic variant has been reported numerous times in association with partial androgen insensitivity syndrome, including in two brothers who had clinical and endocrinological evidence of androgen resistance and developed breast cancer at the ages of 75 and 55 years (Wooster et al., 1992). R608Q 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 R608Q variant is a semi-conservative amino acid substitution, that occurs at a position that is conserved across species. In silico analysis predicts this subsitution is probably damaging to the protein structure/function. Missense variants in nearby residues (T603P, I604N, D605Y, R609K, R609M, N611T) have been reported in the Human Gene Mutation Database in association with androgen insensitivity syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available evidence, we interpret R608Q as a pathogenic variant. -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2021

For these reasons, this variant has been classified as Pathogenic. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9820). This variant has been observed in individual(s) with androgen insensitivity syndrome (PMID: 1303262, 9543136, 10221692, 11788616, 32985417). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 608 of the AR protein (p.Arg608Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Partial androgen insensitivity syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.82
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852573; hg19: chrX-66905906; COSMIC: COSV65954700;