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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000030762OMIM
no assertion criteria provided
Pathogenic
(Sep 1, 2006)
germlineliterature only

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024