Submissions for variant NM_000516.7(GNAS):c.602G>A (p.Arg201His)

gnomAD frequency: 0.00001  dbSNP: rs121913495

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001804738	SCV002051482	pathogenic	not provided	2020-11-20	criteria provided, single submitter	clinical testing	PS3, PS4, PP3, PM2
DASA	RCV001813747	SCV002061301	pathogenic	Pseudohypoparathyroidism type I A	2022-01-05	criteria provided, single submitter	clinical testing	The c.602G>A;p.(Arg201His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 15934; PMID: 25719192; 25157968; 24855271; 23536913; 21835143; 16507630; 15126527; 12727968) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 23403822; 1517386) - PS3_moderate. The variant is present at low allele frequencies population databases (rs121913495– gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (Clivar ID: 210045) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001804738	SCV002563690	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3
Invitae	RCV001804738	SCV003443379	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GNAS protein (p.Arg201His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with McCune–Albright syndrome, as a somatic mosaic variant (PMID: 15126527, 27506760). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15934). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAS protein function. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000017290	SCV004176928	pathogenic	McCune-Albright syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The GNAS c.602G>A (p.Arg201His) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with McCune-Albright syndrome (Pienkowski C et al., PMID: 9343290; Chevalier N et al., PMID: 26321108; Elli FM et al., PMID: 31620168; Román R et al., PMID: 15289771; Lumbroso S et al., PMID: 15126527; Cho EK et al., PMID: 27506760). This variant has been reported in the ClinVar database as a germline pathogenic by multiple submitters (ClinVar ID: 15934). This variant is only observed on 2/152134 alleles in the general population (gnomAD v3.1.2), indicating it is not a common variant. Another variant in the same codon, c.601C>T (p.Arg201Cys), has been reported in multiple affected individuals with McCune-Albright syndrome and is considered pathogenic (Lumbroso S et al., PMID: 15126527; Cho EK et al., PMID: 27506760; ClinVar ID: 15933). The GNAS c.602G>A (p.Arg201His) variant resides within a G-alpha domain, amino acids 41-388, of GNAS that is defined as a critical functional domain (Weinstein LS et al., PMID: 11588148; Tesmer JJ et al., PMID: 9417641). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on GNAS function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAS c.602G>A (p.Arg201His) variant is classified as pathogenic.
Ambry Genetics	RCV004018636	SCV004877045	pathogenic	Inborn genetic diseases	2024-01-30	criteria provided, single submitter	clinical testing	The c.602G>A (p.R201H) alteration is located in exon 8 (coding exon 8) of the GNAS gene. This alteration results from a G to A substitution at nucleotide position 602, causing the arginine (R) at amino acid position 201 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/251454) total alleles studied. The highest observed frequency was 0.01% (1/10078) of Ashkenazi Jewish alleles. This variant was reported in multiple individuals, and as mosaic in some with clinical features such as cafe au lait spots, premature menstruation, neonatal Cushing syndrome, thyroid disease, and others, all consistent with McCune Albright syndrome (Collins, 2003; Lumbroso, 2004; Lourenço, 2015; Coles, 2019). Two other alterations at the same codon, c.601C>A (p.R201S), c.601C>T (p.R201C), and c.601C>G (p.R201G), have been described in individuals with clinical features consistent with McCune Albright syndrome (Riminucci, 1999; Lumbroso, 2004; Jour, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000017290	SCV000037562	pathogenic	McCune-Albright syndrome	2014-05-23	no assertion criteria provided	literature only
OMIM	RCV000017292	SCV000037564	pathogenic	Cushing syndrome	2014-05-23	no assertion criteria provided	literature only
OMIM	RCV000017293	SCV000037565	pathogenic	Sex cord-stromal tumor	2014-05-23	no assertion criteria provided	literature only
GeneReviews	RCV000017290	SCV000246257	not provided	McCune-Albright syndrome		no assertion provided	literature only
Database of Curated Mutations (DoCM)	RCV000430768	SCV000505261	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443822	SCV000506442	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426918	SCV000506443	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437187	SCV000506444	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419515	SCV000506445	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429798	SCV000506446	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436559	SCV000506447	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418739	SCV000506448	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428995	SCV000506449	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439229	SCV000506450	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421581	SCV000506451	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV000508670	SCV000605825	pathogenic	Pituitary adenoma 3, multiple types	2014-05-23	no assertion criteria provided	literature only