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

gnomAD frequency: 0.00001  dbSNP: rs121913495

Total submissions: 12

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
Labcorp Genetics (formerly Invitae), Labcorp	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.
Fulgent Genetics, Fulgent Genetics	RCV005025061	SCV005660928	likely pathogenic	McCune-Albright syndrome; Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pituitary adenoma 3, multiple types; ACTH-independent macronodular adrenal hyperplasia 1; Pseudohypoparathyroidism type I A	2024-06-07	criteria provided, single submitter	clinical testing
OMIM	RCV000017290	SCV000037562	pathogenic	McCune-Albright syndrome	2014-05-23	no assertion criteria provided	literature only
OMIM	RCV004558265	SCV000037564	pathogenic	ACTH-independent macronodular adrenal hyperplasia 1	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
OMIM	RCV000508670	SCV000605825	pathogenic	Pituitary adenoma 3, multiple types	2014-05-23	no assertion criteria provided	literature only