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.
ClinVar Genomic variation as it relates to human health
NM_000516.7(GNAS):c.602G>A (p.Arg201His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000516.7(GNAS):c.602G>A (p.Arg201His)
Variation ID: 15934 Accession: VCV000015934.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.32 20: 58909366 (GRCh38) [ NCBI UCSC ] 20: 57484421 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 22, 2014 Dec 28, 2024 Jan 30, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000516.7:c.602G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000507.1:p.Arg201His missense NM_016592.5:c.*508G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_080425.4:c.2531G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_536350.2:p.Arg844His missense NM_001077488.5:c.605G>A NP_001070956.1:p.Arg202His missense NM_001077489.4:c.557G>A NP_001070957.1:p.Arg186His missense NM_001077490.3:c.*463G>A 3 prime UTR NM_001309840.2:c.425G>A NP_001296769.1:p.Arg142His missense NM_001309861.2:c.425G>A NP_001296790.1:p.Arg142His missense NM_080426.4:c.560G>A NP_536351.1:p.Arg187His missense NC_000020.11:g.58909366G>A NC_000020.10:g.57484421G>A NG_016194.2:g.74627G>A P63092:p.Arg201His - Protein change
- R201H, R186H, R187H, R202H, R844H, R142H
- Other names
- -
- Canonical SPDI
- NC_000020.11:58909365:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00007
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GNAS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
960 | 1117 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Oct 12, 2023 | RCV000017290.16 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV000017293.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV000508670.10 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 15, 2022 | RCV001804738.30 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2022 | RCV001813747.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV004018636.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV004558265.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudohypoparathyroidism type I A
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061301.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
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; … (more)
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. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(Nov 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051482.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 13, 2022 |
Comment:
PS3, PS4, PP3, PM2
|
|
|
Pathogenic
(Mar 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563690.17
First in ClinVar: Aug 23, 2022 Last updated: Dec 28, 2024 |
Comment:
GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443379.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
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). … (more)
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. (less)
|
|
|
Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
McCune-Albright syndrome
Affected status: yes
Allele origin:
somatic
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004176928.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004877045.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
MCCUNE-ALBRIGHT SYNDROME, SOMATIC, MOSAIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000037562.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2014 |
Comment on evidence:
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine … (more)
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2. Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin. Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome. In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene. Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. (less)
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000037564.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 25, 2014 |
Comment on evidence:
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine … (more)
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2. Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin. Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome. In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene. Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. (less)
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
SEX CORD STROMAL TUMOR, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000037565.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2014 |
Comment on evidence:
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine … (more)
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2. Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin. Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome. In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene. Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. (less)
|
|
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Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
PITUITARY ADENOMA 3, GROWTH HORMONE-SECRETING, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000605825.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment on evidence:
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine … (more)
In 2 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) identified an arg201-to-his (R201H) mutation in exon 8 of the GNAS gene in endocrine organs affected in this disorder, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved. In 2 endocrine organs, ovary and adrenal, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. It remained an open question whether GNAS1 mutations were causally related to the nonendocrine abnormalities in 3 of the patients: chronic liver disease in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1, cardiopulmonary disease in 1, and sudden death in 2. Schwindinger et al. (1992) found a G-to-A transition resulting in the R201H substitution in a patient with McCune-Albright syndrome who had severe bony involvement, characteristic skin lesions, and a history of hyperthyroidism. The mutation was found in a higher proportion of skin cells from affected areas than from unaffected areas. The findings confirmed the Happle (1986) hypothesis that this disorder is due to mosaicism for a postzygotic GNAS1 mutation. The authors noted that arg201 is also the site of ADP-ribosylation by the cholera toxin. Collins et al. (2003) identified the R201H mutation in thyroid carcinoma from a patient with McCune-Albright syndrome. In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200) surgically removed from patients with acromegaly, Landis et al. (1989) identified a somatic mutation in the GNAS1 gene, resulting in an R201H substitution. The mutation resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like a dominantly acting oncogene. Fragoso et al. (2003) identified a heterozygous R201H mutation in adrenal tissue from 2 unrelated patients with ACTH-independent macronodular adrenal hyperplasia (219080). Sato et al. (2014) identified a heterozygous somatic R201H mutation in adrenocortical tumors derived from 4 unrelated patients with ACTH-independent Cushing syndrome. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H mutation of the GNAS gene. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. (less)
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not provided
(-)
|
no classification provided
Method: literature only
|
McCune-Albright syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000246257.2
First in ClinVar: Oct 01, 2015 Last updated: Oct 01, 2022 |
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Comment:
Comment:
PS3, PS4, PP3, PM2
Comment:
GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
PS3, PS4, PP3, PM2
Comment:
GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Fibrous Dysplasia / McCune-Albright Syndrome. | Adam MP | - | 2024 | PMID: 25719192 |
| Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. | Li X | Human mutation | 2019 | PMID: 30702195 |
| Severe Neonatal Cholestasis as an Early Presentation of McCune-Albright Syndrome. | Coles N | Journal of clinical research in pediatric endocrinology | 2019 | PMID: 29991465 |
| Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome: a retrospective cohort study. | Cho EK | Orphanet journal of rare diseases | 2016 | PMID: 27506760 |
| Mutational analysis of ATP7B in Chinese Wilson disease patients. | Hua R | American journal of translational research | 2016 | PMID: 27398169 |
| GNAS Mutations in Fibrous Dysplasia: A Comparative Study of Standard Sequencing and Locked Nucleic Acid PCR Sequencing on Decalcified and Nondecalcified Formalin-fixed Paraffin-embedded Tissues. | Jour G | Applied immunohistochemistry & molecular morphology : AIMM | 2016 | PMID: 26574629 |
| Neonatal McCune-Albright syndrome with systemic involvement: a case report. | Lourenço R | Journal of medical case reports | 2015 | PMID: 26341786 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. | Sato Y | Science (New York, N.Y.) | 2014 | PMID: 24855271 |
| Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. | Gu S | PloS one | 2013 | PMID: 23843956 |
| Quantitative and sensitive detection of GNAS mutations causing mccune-albright syndrome with next generation sequencing. | Narumi S | PloS one | 2013 | PMID: 23536913 |
| Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. | Nishikawa G | British journal of cancer | 2013 | PMID: 23403822 |
| GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. | Nault JC | Journal of hepatology | 2012 | PMID: 21835143 |
| Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? | Kalfa N | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16507630 |
| Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. | Margarit E | Clinical genetics | 2005 | PMID: 15952988 |
| Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study. | Lumbroso S | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15126527 |
| Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. | Collins MT | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12970318 |
| Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. | Fragoso MC | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12727968 |
| High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. | García-Villarreal L | Hepatology (Baltimore, Md.) | 2000 | PMID: 11093740 |
| A novel GNAS1 mutation, R201G, in McCune-albright syndrome. | Riminucci M | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 1999 | PMID: 10571700 |
| Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. | Schwindinger WF | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1594625 |
| Glycoprotein hormone alpha-subunit production in somatotroph adenomas with and without Gs alpha mutations. | Harris PE | The Journal of clinical endocrinology and metabolism | 1992 | PMID: 1517386 |
| Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. | Weinstein LS | The New England journal of medicine | 1991 | PMID: 1944469 |
| GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. | Landis CA | Nature | 1989 | PMID: 2549426 |
| The McCune-Albright syndrome: a lethal gene surviving by mosaicism. | Happle R | Clinical genetics | 1986 | PMID: 3720010 |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Jul 31, 2024 | RCV000430768.11 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094026.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
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.
Comment:
PS3, PS4, PP3, PM2
Comment:
GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3
Comment:
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.
Comment:
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.
Comment:
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.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs121913495 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.