NM_000516.7(GNAS):c.772C>T (p.Arg258Trp) AND Pseudopseudohypoparathyroidism

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 6, 2017
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:: RCV000017306.25

Allele description [Variation Report for NM_000516.7(GNAS):c.772C>T (p.Arg258Trp)]

NM_000516.7(GNAS):c.772C>T (p.Arg258Trp)

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.772C>T (p.Arg258Trp)

HGVS:

NC_000020.11:g.58909737C>T
NG_016194.2:g.74998C>T
NM_000516.7:c.772C>TMANE SELECT
NM_001077488.5:c.775C>T
NM_001077489.4:c.727C>T
NM_001077490.3:c.*633C>T
NM_001309840.2:c.595C>T
NM_001309861.2:c.595C>T
NM_016592.5:c.*678C>T
NM_080425.4:c.2701C>T
NM_080426.4:c.730C>T
NP_000507.1:p.Arg258Trp
NP_001070956.1:p.Arg259Trp
NP_001070957.1:p.Arg243Trp
NP_001296769.1:p.Arg199Trp
NP_001296790.1:p.Arg199Trp
NP_536350.2:p.Arg901Trp
NP_536351.1:p.Arg244Trp
NC_000020.10:g.57484792C>T
NM_000516.4:c.772C>T

Protein change:

R199W; ARG258TRP

Links:

OMIM: 139320.0016; dbSNP: rs137854535

NCBI 1000 Genomes Browser:

rs137854535

Molecular consequence:

NM_001077490.3:c.*633C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_016592.5:c.*678C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000516.7:c.772C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077488.5:c.775C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077489.4:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001309840.2:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001309861.2:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080425.4:c.2701C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080426.4:c.730C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pseudopseudohypoparathyroidism (PPHP)
Synonyms:: Albright hereditary osteodystrophy without multiple hormone resistance
Identifiers:: MONDO: MONDO:0012912; MedGen: C0033835; Orphanet: 79445; OMIM: 612463

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000037578	OMIM	no assertion criteria provided	Pathogenic (Sep 11, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000586752	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2017)	de novo	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9727013, 25741868, 28708303

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000037578

OMIM

no assertion criteria provided

Pathogenic
(Sep 11, 1998)

germline

literature only

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

SCV000586752

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 6, 2017)

de novo

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation.

Warner DR, Weng G, Yu S, Matalon R, Weinstein LS.

J Biol Chem. 1998 Sep 11;273(37):23976-83.

PubMed [citation]

PMID:: 9727013

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000037578.2

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

Description

In a 24-year-old man with PPHP (612463), Warner et al. (1998) identified a de novo arg258-to-trp (R258W) mutation in the GNAS1 gene. Arg258 is a nonconserved residue adjacent to a highly conserved glutamic acid residue, glu259, that is important for contact between switch 2 and 3 in the activated state. Warner et al. (1998) presented evidence that substitution of arg258 led to defective GDP binding, resulting in increased thermolability and decreased activation. Developmental delay, brachycephaly, and decreased muscle tone were noted by age 10 months. Throughout childhood he was small for his age and stocky in appearance. By 6 years, he developed learning disabilities as well as impulsive and aggressive behavior. Brachydactyly involved the distal phalanx of the thumb and the fourth metacarpals bilaterally. He also had intracranial calcifications in the globus pallidus. There was no evidence of resistance to parathyroid hormone or thyrotropin.

#	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

From Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris, SCV000586752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

Intellectual disability; small stature

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

Last Updated: Oct 20, 2024

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