NM_000516.7(GNAS):c.691C>T (p.Arg231Cys) AND Pseudohypoparathyroidism type I A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002283517.2

Allele description [Variation Report for NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)]

NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)

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.691C>T (p.Arg231Cys)

HGVS:

NC_000020.11:g.58909552C>T
NG_016194.2:g.74813C>T
NM_000516.7:c.691C>TMANE SELECT
NM_001077488.5:c.694C>T
NM_001077489.4:c.646C>T
NM_001077490.3:c.*552C>T
NM_001309840.2:c.514C>T
NM_001309861.2:c.514C>T
NM_016592.5:c.*597C>T
NM_080425.4:c.2620C>T
NM_080426.4:c.649C>T
NP_000507.1:p.Arg231Cys
NP_000507.1:p.Arg231Cys
NP_001070956.1:p.Arg232Cys
NP_001070957.1:p.Arg216Cys
NP_001296769.1:p.Arg172Cys
NP_001296790.1:p.Arg172Cys
NP_536350.2:p.Arg874Cys
NP_536351.1:p.Arg217Cys
NC_000020.10:g.57484607C>T
NC_000020.10:g.57484607C>T
NM_000516.4:c.691C>T
NM_000516.5:c.691C>T
NM_000516.6:c.691C>T

Protein change:

R172C

Links:

dbSNP: rs1601162438

NCBI 1000 Genomes Browser:

rs1601162438

Molecular consequence:

NM_001077490.3:c.*552C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_016592.5:c.*597C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000516.7:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077488.5:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077489.4:c.646C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001309840.2:c.514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001309861.2:c.514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080425.4:c.2620C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080426.4:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pseudohypoparathyroidism type I A (PHP1A)
Synonyms:: PHP IA; Pseudohypoparathyroidism type 1A; Albright hereditary osteodystrophy with multiple hormone resistance; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007078; MedGen: C3494506; OMIM: 103580

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002573121	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8702665, 25741868
SCV004242453	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 28, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002573121

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004242453

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 28, 2019)

unknown

clinical testing

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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gsalpha impairs receptor stimulation.

Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M, Bourne HR.

J Biol Chem. 1996 Aug 16;271(33):19653-5.

PubMed [citation]

PMID:: 8702665

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

Details of each submission

From 3billion, SCV002573121.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000816910). A different missense change at the same codon (p.Arg231His) has been reported to be associated with GNAS-related disorder (ClinVar ID: VCV000015946 / PMID: 8702665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004242453.1

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

Description

Criteria applied: PS4, PS2_MOD, PM5, PM2_SUP, PP2,PP3

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

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine