ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs11554273
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV002513071 SCV005198404 pathogenic not provided 2023-03-08 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV004760335 SCV005374279 likely pathogenic Pseudohypoparathyroidism type 1B 2024-09-22 criteria provided, single submitter clinical testing
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 RCV004558264 SCV000188577 pathogenic ACTH-independent macronodular adrenal hyperplasia 1 2014-05-23 no assertion criteria provided literature only
GeneReviews RCV000017287 SCV000246254 not provided McCune-Albright syndrome no assertion 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

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