NM_000044.6(AR):c.2296G>A (p.Ala766Thr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000791383.6

Allele description [Variation Report for NM_000044.6(AR):c.2296G>A (p.Ala766Thr)]

NM_000044.6(AR):c.2296G>A (p.Ala766Thr)

Gene:

AR:androgen receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq12

Genomic location:

Preferred name:

NM_000044.6(AR):c.2296G>A (p.Ala766Thr)

HGVS:

NC_000023.11:g.67717600G>A
NG_009014.2:g.178569G>A
NM_000044.6:c.2296G>AMANE SELECT
NM_001011645.3:c.700G>A
NP_000035.2:p.Ala766Thr
NP_001011645.1:p.Ala234Thr
LRG_1406t1:c.2296G>A
LRG_1406:g.178569G>A
LRG_1406p1:p.Ala766Thr
NC_000023.10:g.66937442G>A
NM_000044.3:c.2296G>A
NM_000044.4:c.2296G>A

Protein change:

A234T

Links:

dbSNP: rs1555996863

NCBI 1000 Genomes Browser:

rs1555996863

Molecular consequence:

NM_000044.6:c.2296G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001011645.3:c.700G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Androgen resistance syndrome (AIS)
Synonyms:: TESTICULAR FEMINIZATION SYNDROME; Androgen insensitivity syndrome; Androgen receptor deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019154; MedGen: C0039585; Orphanet: 99429; OMIM: 300068

Name:: Kennedy disease (SMAX1)
Synonyms:: SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; Bulbo-spinal atrophy X-linked; Kennedy spinal and bulbar muscular atrophy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010735; MedGen: C1839259; Orphanet: 481; OMIM: 313200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000629590	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 1307250, 8723113, 9328206, 9856504, 10690872, 15531547, 15925895, 25248670, 25613104, 27899157, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629590

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 9, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.

Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA, Patterson MN.

Hum Mol Genet. 1992 Oct;1(7):497-503.

PubMed [citation]

PMID:: 1307250

The clinical and molecular spectrum of androgen insensitivity syndromes.

Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K.

Am J Med Genet. 1996 May 3;63(1):218-22.

PubMed [citation]

PMID:: 8723113

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000629590.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 1307250, 9328206, 9856504, 10690872, 15531547). 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: 458363). This missense change has been observed in individuals with complete androgen insensitivity syndrome (PMID: 1307250, 8723113, 9328206, 9856504, 10690872, 15531547, 15925895, 25248670, 25613104, 27899157). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 766 of the AR protein (p.Ala766Thr).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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