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NM_000516.7(GNAS):c.1096G>T (p.Ala366Ser) AND PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 8, 1994
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:
RCV000017309.27

Allele description [Variation Report for NM_000516.7(GNAS):c.1096G>T (p.Ala366Ser)]

NM_000516.7(GNAS):c.1096G>T (p.Ala366Ser)

Gene:
GNAS:GNAS complex locus [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.32
Genomic location:
Preferred name:
NM_000516.7(GNAS):c.1096G>T (p.Ala366Ser)
HGVS:
  • NC_000020.11:g.58910740G>T
  • NG_016194.2:g.76001G>T
  • NM_000516.7:c.1096G>TMANE SELECT
  • NM_001077488.5:c.1099G>T
  • NM_001077489.4:c.1051G>T
  • NM_001077490.3:c.*957G>T
  • NM_001309840.2:c.919G>T
  • NM_001309861.2:c.919G>T
  • NM_016592.5:c.*1002G>T
  • NM_080425.4:c.3025G>T
  • NM_080426.4:c.1054G>T
  • NP_000507.1:p.Ala366Ser
  • NP_001070956.1:p.Ala367Ser
  • NP_001070957.1:p.Ala351Ser
  • NP_001296769.1:p.Ala307Ser
  • NP_001296790.1:p.Ala307Ser
  • NP_536350.2:p.Ala1009Ser
  • NP_536351.1:p.Ala352Ser
  • NC_000020.10:g.57485795G>T
Protein change:
A1009S; ALA366SER
Links:
OMIM: 139320.0019; dbSNP: rs137854537
NCBI 1000 Genomes Browser:
rs137854537
Molecular consequence:
  • NM_001077490.3:c.*957G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_016592.5:c.*1002G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000516.7:c.1096G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077488.5:c.1099G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077489.4:c.1051G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001309840.2:c.919G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001309861.2:c.919G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080425.4:c.3025G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080426.4:c.1054G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS
Identifiers:
MedGen: C4016140

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000037581OMIM
no assertion criteria provided
Pathogenic
(Sep 8, 1994) 		germlineliterature only

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

Help

Summary from all submissions

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

Citations

PubMed

Rapid GDP release from Gs alpha in patients with gain and loss of endocrine function.

Iiri T, Herzmark P, Nakamoto JM, van Dop C, Bourne HR.

Nature. 1994 Sep 8;371(6493):164-8.

PubMed [citation]
PMID:
8072545

Details of each submission

From OMIM, SCV000037581.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Iiri et al. (1994) studied 2 unrelated boys who had a paradoxical combination of PHP Ia (103580) and testotoxicosis (176410). Both boys were found to have an ala366-to-ser (A366S) mutation in the GNAS1 gene. PHP Ia is marked by resistance to hormones acting through cyclic AMP (parathyroid hormone and thyroid-stimulating hormone) as well as a 50% decrease in erythrocyte Gs activity in this heterozygous disorder. In contrast, testotoxicosis is a form of precocious puberty in which the Leydig cells secrete testosterone in the absence of luteinizing hormone, often due to constitutive activation of the luteinizing hormone receptor and (indirectly) of Gs. Iiri et al. (1994) demonstrated that this A366S mutation constitutively activated adenylyl cyclase in vitro, causing hormone-independent cAMP accumulation when expressed in cultured cells, and accounting for the testotoxicosis phenotype. Although the mutant form was quite stable at testis temperature, it was rapidly degraded at 37 degrees centigrade, explaining the PHP Ia phenotype caused by loss of Gs activity. In vitro experiments indicated that accelerated release of GDP caused both the constitutive activity and the thermolability of the A366S mutant form.

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

Last Updated: Sep 17, 2022