Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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, |
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, |
RCV002513071 | SCV005198404 | pathogenic | not provided | 2023-03-08 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
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 | |
Gene |
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, |
RCV000017287 | SCV000804872 | pathogenic | McCune-Albright syndrome | 2014-02-14 | no assertion criteria provided | clinical testing |