rs121913495
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000516.7(GNAS):c.602G>A(p.Arg201His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201G) has been classified as Pathogenic.
Frequency
Consequence
NM_000516.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNAS | NM_080425.4 | c.2531G>A | p.Arg844His | missense_variant | 8/13 | ENST00000371100.9 | |
GNAS | NM_000516.7 | c.602G>A | p.Arg201His | missense_variant | 8/13 | ENST00000371085.8 | |
GNAS | NM_016592.5 | c.*508G>A | 3_prime_UTR_variant | 8/13 | ENST00000371075.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371100.9 | c.2531G>A | p.Arg844His | missense_variant | 8/13 | 5 | NM_080425.4 | ||
GNAS | ENST00000371085.8 | c.602G>A | p.Arg201His | missense_variant | 8/13 | 1 | NM_000516.7 | ||
GNAS | ENST00000371075.7 | c.*508G>A | 3_prime_UTR_variant | 8/13 | 1 | NM_016592.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1460964Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 726854
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 20, 2020 | PS3, PS4, PP3, PM2 - |
McCune-Albright syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 23, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 12, 2023 | 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. - |
Adrenal cortex carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | 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. - |
Pseudohypoparathyroidism type I A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | 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. - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pituitary adenoma 3, multiple types Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 23, 2014 | - - |
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Sex cord-stromal tumor Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 23, 2014 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
ACTH-independent macronodular adrenal hyperplasia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 23, 2014 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at