NM_000044.6(AR):c.1937C>A (p.Ala646Asp) AND Partial androgen insensitivity syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 1, 2006
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000010536.3

Allele description [Variation Report for NM_000044.6(AR):c.1937C>A (p.Ala646Asp)]

NM_000044.6(AR):c.1937C>A (p.Ala646Asp)

Gene:

AR:androgen receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq12

Genomic location:

Preferred name:

NM_000044.6(AR):c.1937C>A (p.Ala646Asp)

Other names:

AR, ALA645ASP, SHORT POLYGLYCINE REPEAT, LONG POLYGLUTAMINE REPEAT; A645D

HGVS:

NC_000023.11:g.67711453C>A
NG_009014.2:g.172422C>A
NM_000044.3:c.1937C>A
NM_000044.6:c.1937C>AMANE SELECT
NM_001011645.3:c.341C>A
NP_000035.2:p.Ala646Asp
NP_001011645.1:p.Ala114Asp
LRG_1406t1:c.1937C>A
LRG_1406:g.172422C>A
LRG_1406p1:p.Ala646Asp
NC_000023.10:g.66931295C>A
NM_000044.2:c.1937C>A
NM_000044.6:c.1937C>A
P10275:p.Ala646Asp

Protein change:

A114D; ALA645ASP

Links:

UniProtKB: P10275#VAR_004686; OMIM: 313700.0060; dbSNP: rs1800053

NCBI 1000 Genomes Browser:

rs1800053

Molecular consequence:

NM_000044.6:c.1937C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001011645.3:c.341C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Partial androgen insensitivity syndrome (PAIS)
Synonyms:: ANDROGEN INSENSITIVITY, PARTIAL, WITH OR WITHOUT BREAST CANCER; Gynecomastia, familial; Pseudohermaphroditism, Incomplete male, type I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010720; MedGen: C0268301; Orphanet: 90797; OMIM: 312300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030762	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000030762

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2006)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats.

Werner R, Holterhus PM, Binder G, Schwarz HP, Morlot M, Struve D, Marschke C, Hiort O.

J Clin Endocrinol Metab. 2006 Sep;91(9):3515-20. Epub 2006 Jun 27.

PubMed [citation]

PMID:: 16804045

Details of each submission

From OMIM, SCV000030762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Werner et al. (2006) reported 2 unrelated 46,XY patients with undervirilization and genital malformations. Both patients had a short polyglycine (polyG) repeat of 10 residues and a relatively long polyglutamine (polyQ) repeat of 28 and 30 residues in the transactivation domain of the AR. In addition, both had a rare ala645-to-asp (A645D) substitution. In studies in transfected CHO cells, Werner et al. (2006) found that a short polyG repeat downmodulated AR activity to approximately 60 to 65% of the wildtype receptor. This effect was aggravated by A645D in context of a long polyQ repeat to less than 50% activity. In contrast, in the context of a short polyQ and a short polyG repeat, the A645D mutation rescues AR activity to almost wildtype levels, demonstrating a contradictory effect of this mutation, depending on the size of the polymorphic repeats. Werner et al. (2006) concluded that a combination of a short polyG repeat with a long polyQ repeat and an A645D substitution might explain the observed phenotype of their patients as a form of androgen insensitivity.

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

Last Updated: Oct 20, 2024

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