Submissions for variant NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)

gnomAD frequency: 0.00001  dbSNP: rs11554273

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002513071	SCV003272248	pathogenic	not provided	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). 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. ClinVar contains an entry for this variant (Variation ID: 15933). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000017287	SCV004176911	pathogenic	McCune-Albright syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic.
OMIM	RCV000017287	SCV000037559	pathogenic	McCune-Albright syndrome	2014-05-23	no assertion criteria provided	literature only
OMIM	RCV000017289	SCV000037561	pathogenic	Sex cord-stromal tumor	2014-05-23	no assertion criteria provided	literature only
OMIM	RCV000133503	SCV000188577	pathogenic	Cushing syndrome	2014-05-23	no assertion criteria provided	literature only
GeneReviews	RCV000017287	SCV000246254	not provided	McCune-Albright syndrome		no assertion provided	literature only
Database of Curated Mutations (DoCM)	RCV000420084	SCV000505260	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429524	SCV000506432	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439728	SCV000506433	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422043	SCV000506434	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432295	SCV000506435	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444862	SCV000506436	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421422	SCV000506437	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431495	SCV000506438	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443647	SCV000506439	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427542	SCV000506440	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437784	SCV000506441	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV000508635	SCV000605824	pathogenic	Pituitary adenoma 3, multiple types	2014-05-23	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000017287	SCV000804872	pathogenic	McCune-Albright syndrome	2014-02-14	no assertion criteria provided	clinical testing