About GNAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GNAS c.602G>A, p.(Arg201His)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS3Strong
PS3 · strong
Well-established functional studies demonstrate that p.Arg201His constitutively activates Gsα. Landis et al. (PMID:2549426) showed that R201H substitution reduces GTPase activity approximately 30-fold, resulting in constitutive adenylyl cyclase activation. Taki et al. (PMID:26257060) demonstrated that transgenic expression of GNAS R201H in murine pancreas elevates cAMP levels, induces ductal dilation, and cooperates with KrasG12D to promote tumorigenesis recapitulating human IPMN. Two independent publications with direct variant-specific functional characterization satisfy PS3 at strong strength.
PS4Moderate
PS4 · moderate
This variant has been reported in numerous unrelated individuals with McCune-Albright syndrome and related phenotypes. Lumbroso et al. (PMID:15126527) identified R201H in 34 of 113 patients with MAS signs, representing the most common activating mutation. The variant is classified as Pathogenic in ClinVar by multiple clinical laboratories (Variation ID 15934). gnomAD population frequency is extremely low (AF=0.00159%; 4/251,454 alleles in v2.1), demonstrating significant enrichment in affected individuals compared to population controls. Strength is calibrated to moderate given the predominantly somatic mosaic context.
PM1Moderate
PM1 · moderate
The variant resides at codon 201 within the GTPase domain of Gsα, a critical functional domain. Arg201 is the site of ADP-ribosylation by cholera toxin and is essential for intrinsic GTPase activity. The codon is a well-established mutational hotspot in McCune-Albright syndrome, pituitary adenomas, and other tumors. Cancerhotspots.org identifies this residue as statistically significant. The variant lies within a domain where essentially all reported missense changes are pathogenic.
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases. gnomAD v2.1 exomes: allele frequency 1.59×10⁻⁵ (0.00159%; 4/251,454 alleles, 0 homozygotes). gnomAD v4.1: allele frequency 2.48×10⁻⁵ (40/1,613,098 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0.
PM5Moderate
PM5 · moderate
A different missense change at the same amino acid residue (p.Arg201Cys, resulting from c.601C>T) is well-established as pathogenic. R201C is the second most common activating GNAS mutation in McCune-Albright syndrome and related disorders, with equivalent gain-of-function consequences. Lumbroso et al. (PMID:15126527) reported R201C in 15/113 patients. Both R201H and R201C are established activating mutations that disrupt GTPase activity and constitutively activate adenylyl cyclase.
PP3Supporting
PP3 · supporting
Multiple lines of computational evidence support a deleterious effect. REVEL score is 0.969, which is strongly predictive of pathogenicity. BayesDel score is 0.612, consistent with a damaging prediction. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a missense variant not near splice junctions. The REVEL score in particular provides strong in silico support.
PP5Supporting
PP5 · supporting
This variant is reported as Pathogenic in ClinVar (Variation ID 15934) by multiple clinical laboratories: 6 classify as Pathogenic and 3 as Likely pathogenic. While the aggregate review status is 'criteria provided, single submitter' (no expert panel review), the consensus across multiple independent laboratories provides supporting evidence for pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; combination = 1 strong + 3 moderate + 3 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
40 / 1,613,098 alleles
gnomAD v4.1: 40 / 1,613,098 alleles. Recorded AF 2.4797e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59075e-05; MAF= 0.00159%, 4/251454 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.9226e-05; MAF= 0.00992%, 1/10078 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
9 reported laboratory submissions
6 Pathogenic · 3 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 7 met · 16 not met · 1 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000516.5:c.602G>A (p.Arg201His) is a well-characterized activating missense variant in the GNAS gene. Functional studies demonstrate that this substitution reduces GTPase activity approximately 30-fold, causing constitutive activation of adenylyl cyclase and downstream cAMP signaling (PS3_Strong).
The variant resides at codon 201 within the GTPase domain of Gsα, a critical functional domain and established mutational hotspot (PM1_Moderate).
A different pathogenic missense change at the same residue, p.Arg201Cys, is well-established in McCune-Albright syndrome and functionally equivalent (PM5_Moderate).
The variant has been reported in numerous individuals with McCune-Albright syndrome; Lumbroso et al. identified R201H in 34 of 113 patients with MAS features (PS4_Moderate).
The variant is extremely rare in population databases (gnomAD v2.1 AF=0.00159%), supporting pathogenicity (PM2_Supporting).
Computational predictors strongly support a deleterious effect: REVEL score 0.969, BayesDel score 0.612 (PP3_Supporting).
ClinVar classifies this variant as Pathogenic (Variation ID 15934) with consensus across multiple clinical laboratories (PP5_Supporting).
Applying the generic ACMG/AMP 2015 combination rules: one Strong criterion (PS3) plus three Moderate criteria (PM1, PM5, PS4) and three Supporting criteria (PM2, PP3, PP5) meets the threshold for Pathogenic classification.
No criteria match.
Met · 7
PS3 StrongWell-established functional studies demonstrate that p.Arg201His constitutively activates Gsα. Landis et al. (PMID:2549426) showed that R201H substitution reduces GTPase activity approximately 30-fold, resulting in constitutive adenylyl cyclase activation. Taki et al. (PMID:26257060) demonstrated that transgenic expression of GNAS R201H in murine pancreas elevates cAMP levels, induces ductal dilation, and cooperates with KrasG12D to promote tumorigenesis recapitulating human IPMN. Two independent publications with direct variant-specific functional characterization satisfy PS3 at strong strength. Details ▾Hide ▴
Evidence considered
- In vitro mutagenesis: R201H reduces GTPase activity ~30-fold with constitutive adenylyl cyclase activation (PMID:2549426).
- In vivo mouse model: GNAS R201H expression elevates cAMP and promotes pancreatic tumorigenesis (PMID:26257060).
- OncoKB classification: Oncogenic
- gain-of-function.
- PMID:1594625 confirms R201H identification in MAS and describes prior functional characterization.
Sources
PS4 ModerateThis variant has been reported in numerous unrelated individuals with McCune-Albright syndrome and related phenotypes. Lumbroso et al. (PMID:15126527) identified R201H in 34 of 113 patients with MAS signs, representing the most common activating mutation. The variant is classified as Pathogenic in ClinVar by multiple clinical laboratories (Variation ID 15934). gnomAD population frequency is extremely low (AF=0.00159%; 4/251,454 alleles in v2.1), demonstrating significant enrichment in affected individuals compared to population controls. Strength is calibrated to moderate given the predominantly somatic mosaic context. Details ▾Hide ▴
Evidence considered
- 34/113 patients with MAS signs carry R201H (PMID:15126527).
- Multiple independent case reports and series document R201H in MAS.
- ClinVar: 6 labs classify as Pathogenic
- 3 as Likely pathogenic.
- gnomAD v2.1: extremely low population frequency (0.00159%).
Sources
PM1 ModerateThe variant resides at codon 201 within the GTPase domain of Gsα, a critical functional domain. Arg201 is the site of ADP-ribosylation by cholera toxin and is essential for intrinsic GTPase activity. The codon is a well-established mutational hotspot in McCune-Albright syndrome, pituitary adenomas, and other tumors. Cancerhotspots.org identifies this residue as statistically significant. The variant lies within a domain where essentially all reported missense changes are pathogenic. Details ▾Hide ▴
Evidence considered
- Codon 201 is in the GTPase domain of Gsα
- critical for GTP hydrolysis.
- Arg201 is the site of cholera toxin ADP-ribosylation that inactivates GTPase.
- Statistically significant hotspot residue at cancerhotspots.org.
- OncoKB notes location within a critical functional domain.
Sources
PM2 SupportingThis variant is present at extremely low frequency in population databases. gnomAD v2.1 exomes: allele frequency 1.59×10⁻⁵ (0.00159%; 4/251,454 alleles, 0 homozygotes). gnomAD v4.1: allele frequency 2.48×10⁻⁵ (40/1,613,098 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=1.59e-05 (4/251
- 454 alleles).
- gnomAD v4.1: AF=2.48e-05 (40/1
- 613
- 098 alleles).
- gnomAD-Canada: absent.
- Highest subpopulation AF: Ashkenazi Jewish 9.92e-05 (1/10
- 078).
- No homozygotes observed in any population database.
Sources
PM5 ModerateA different missense change at the same amino acid residue (p.Arg201Cys, resulting from c.601C>T) is well-established as pathogenic. R201C is the second most common activating GNAS mutation in McCune-Albright syndrome and related disorders, with equivalent gain-of-function consequences. Lumbroso et al. (PMID:15126527) reported R201C in 15/113 patients. Both R201H and R201C are established activating mutations that disrupt GTPase activity and constitutively activate adenylyl cyclase. Details ▾Hide ▴
Evidence considered
- R201C (c.601C>T) is a well-established pathogenic missense at the same codon.
- PMID:15126527: R201C found in 15/49 mutation-positive MAS patients.
- PMID:2549426: R201C also characterized as activating with GTPase inhibition.
Sources
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score is 0.969, which is strongly predictive of pathogenicity. BayesDel score is 0.612, consistent with a damaging prediction. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a missense variant not near splice junctions. The REVEL score in particular provides strong in silico support. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.969 (strongly pathogenic).
- BayesDel score: 0.612 (damaging).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
PP5 SupportingThis variant is reported as Pathogenic in ClinVar (Variation ID 15934) by multiple clinical laboratories: 6 classify as Pathogenic and 3 as Likely pathogenic. While the aggregate review status is 'criteria provided, single submitter' (no expert panel review), the consensus across multiple independent laboratories provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 15934: classified as Pathogenic.
- 6 clinical laboratories report Pathogenic
- 3 report Likely pathogenic.
- Review status: criteria provided
- single submitter (no expert panel).
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change (p.Arg201His) resulting from a different nucleotide change. The canonical R201H alteration arises exclusively from c.602G>A; no alternative nucleotide substitution yielding p.Arg201His has been reported. Other pathogenic changes at codon 201 result in different amino acid substitutions (R201C, R201S, R201G, R201L). Details ▾Hide ▴
Evidence considered
- R201H is produced by a single nucleotide substitution (c.602G>A).
- Other codon 201 mutations (R201C
- R201S
- R201G
- R201L) produce different amino acid changes.
Sources
PS2 No confirmed de novo occurrence with both maternity and paternity confirmed has been identified for this variant in a germline context. GNAS p.Arg201His is predominantly a postzygotic somatic mosaic mutation causing McCune-Albright syndrome. Details ▾Hide ▴
Evidence considered
- GNAS R201H arises as a postzygotic somatic mutation in MAS.
- No de novo germline report with confirmed parentage was identified.
Sources
PM6 PM6 applies when a variant is assumed de novo but without confirmation of paternity and maternity. No de novo germline report was identified for this variant. GNAS p.Arg201His in McCune-Albright syndrome is a postzygotic somatic mosaic event, not a germline de novo mutation. Details ▾Hide ▴
Evidence considered
- No de novo germline report identified.
- MAS-associated GNAS mutations are postzygotic somatic events.
Sources
PP1 No cosegregation data are available for this variant in a germline context. McCune-Albright syndrome is a sporadic disorder caused by postzygotic somatic mutations; familial inheritance is not expected. Details ▾Hide ▴
Evidence considered
- MAS is a sporadic disorder with no documented inheritance.
- No cosegregation data available.
Sources
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient-specific phenotype data are available for this assessment. This criterion is evaluated in the context of the individual being tested, not at the variant level. Details ▾Hide ▴
Evidence considered
- No patient-specific phenotype information provided for this case.
Still missing
- Patient phenotype data not available.
BA1 BA1 requires allele frequency >1% in population databases. This variant has an allele frequency of 0.00159% in gnomAD v2.1 and 0.00248% in gnomAD v4.1, both far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00159% (<<1%).
- gnomAD v4.1 AF: 0.00248% (<<1%).
Sources
BS1 BS1 requires allele frequency >0.3% in population databases. This variant has an allele frequency of 0.00159% in gnomAD v2.1 and 0.00248% in gnomAD v4.1, both far below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00159% (<<0.3%).
- gnomAD v4.1 AF: 0.00248% (<<0.3%).
Sources
BS2 BS2 requires observation in healthy adults at significant frequency. This variant is present at only 4/251,454 alleles in gnomAD v2.1 with no homozygotes. The extremely low frequency does not support a benign interpretation. No evidence of healthy adult homozygotes or high-frequency carriers exists. Details ▾Hide ▴
Evidence considered
- Extremely rare in populations (0.00159% in gnomAD v2.1).
- No homozygotes observed.
Sources
BS3 BS3 requires well-established functional studies showing no damaging effect. The functional data for p.Arg201His consistently demonstrate a gain-of-function activating effect: reduced GTPase activity (~30-fold), constitutive adenylyl cyclase activation, elevated cAMP, and promotion of tumorigenesis in vivo. The evidence supports pathogenicity, not benignity. Details ▾Hide ▴
Evidence considered
- Functional studies demonstrate gain-of-function constitutive activation.
- PMID:2549426: ~30-fold GTPase reduction.
- PMID:26257060: elevated cAMP and tumorigenesis in mouse model.
- OncoKB: oncogenic
- gain-of-function.
- Evidence supports damaging effect
- opposite of BS3 requirement.
Sources
BS4 BS4 requires lack of segregation in affected family members. No segregation data are available. McCune-Albright syndrome is a sporadic postzygotic disorder; lack of segregation is not informative for benignity. Details ▾Hide ▴
Evidence considered
- MAS is a sporadic somatic mosaic disorder.
- No multigenerational segregation data available or expected.
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. GNAS has a well-established gain-of-function disease mechanism through activating missense mutations (McCune-Albright syndrome, endocrine tumors) in addition to loss-of-function through truncating variants (pseudohypoparathyroidism). Missense variants at codon 201 are the primary cause of MAS. Details ▾Hide ▴
Evidence considered
- GNAS gain-of-function missense mutations cause MAS.
- Codon 201 missense variants are the primary pathogenic mechanism in MAS.
Sources
BP2 BP2 requires observation in trans with a pathogenic variant in a gene associated with a recessive disorder. GNAS-related disorders are dominant; BP2 does not apply. No evidence of in trans configuration with another pathogenic GNAS variant exists. Details ▾Hide ▴
Evidence considered
- GNAS disorders are dominantly acting.
- No evidence of in trans configuration.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.969 strongly predicts pathogenicity. BayesDel score of 0.612 supports a damaging effect. While SpliceAI predicts no splicing impact (delta 0.01), the overall in silico profile supports a deleterious effect, opposite of BP4 requirements. Details ▾Hide ▴
Evidence considered
- REVEL 0.969: strongly pathogenic prediction.
- BayesDel 0.612: damaging prediction.
- SpliceAI 0.01: no splice impact
- but does not offset deleterious missense predictions.
Sources
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No evidence of an alternative molecular diagnosis exists for cases carrying this variant. GNAS R201H is the established molecular cause in reported cases. Details ▾Hide ▴
Evidence considered
- GNAS R201H is the established molecular cause in reported MAS cases.
- No alternate molecular basis identified.
BP6 BP6 requires a reputable source to report the variant as benign. ClinVar classifies this variant as Pathogenic (Variation ID 15934). No reputable source reports it as benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic.
- No reputable source classifies as benign.
Sources
BP7 BP7 applies to synonymous variants with no predicted splice impact. NM_000516.5:c.602G>A is a missense variant producing p.Arg201His, not a synonymous change. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- This is a missense variant (p.Arg201His)
- not synonymous.
Not assessed · 1 · no assessment recorded
PP2 PP2 requires that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. GNAS has a dual disease mechanism: gain-of-function missense variants cause McCune-Albright syndrome and related disorders, while loss-of-function variants (including truncating) cause pseudohypoparathyroidism. The gene-level constraint metrics for PP2 were not systematically evaluated for this assessment. Details ▾Hide ▴
Evidence considered
- GNAS has both gain-of-function (missense) and loss-of-function disease mechanisms.
- Gene-level benign missense constraint not systematically evaluated.
Still missing
- Gene-level missense constraint metrics (e.g.
- gnomAD Z-score
- missense o/e ratio) not evaluated.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000516.5:c.602G>A is a missense variant (p.Arg201His) that does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 201
- not a null variant.
- pvs1_variant_assessment confirms variant bucket is 'other'
- apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No CSPEC/VCEP or custom gene-specific framework defines this criterion for GNAS. The standard ACMG framework extends from PVS1 through BP7 only. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG criterion
- no custom framework defines PS5 for GNAS.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- GNAS
- Transcript
- NM_000516.5
- Coding (HGVS c.)
- NM_000516.5:c.602G>A
- Protein (HGVS p.)
- NP_000507.1:p.(Arg201His)
- GRCh38
- chr20:58909366 G>A
- GRCh37
- chr20:57484421 G>A
- ClinVar
- 15934
Gene diagram
Every interpreted variant in GNAS, mapped onto the exon structure of NM_000516.5. Select a row to find it on the plot.
GNASNM_000516.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GNAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
40 / 1,613,098 alleles
AF 2.48e-05 · 0 homozygotes · FAF 2.15e-05
gnomAD v2.1
4 / 251,454 alleles
AF 1.59e-05 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-05 · 40 / 1,613,098 alleles · 0 hom · FAF 2.2e-05
| Ashkenazi Jewish2 / 29,600 | 6.8e-05 |
| European (non-Finnish)35 / 1,179,206 | 3e-05 |
| Admixed American1 / 60,004 | 1.7e-05 |
| African/African American1 / 74,888 | 1.3e-05 |
| South Asian1 / 91,056 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern.
gnomAD v2.1
AF 1.6e-05 · 4 / 251,454 alleles · 0 hom · FAF 2.9e-06
| Ashkenazi Jewish1 / 10,078 | 9.9e-05 |
| Admixed American1 / 34,588 | 2.9e-05 |
| European (non-Finnish)2 / 113,754 | 1.8e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.4797e-05; MAF= 0.00248%, 40/1613098 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 6.75676e-05; MAF= 0.00676%, 2/29600 alleles, homozygotes = 0); grpmax FAF= 2.155e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59075e-05; MAF= 0.00159%, 4/251454 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.9226e-05; MAF= 0.00992%, 1/10078 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.969
- BayesDel
- 0.612
How the predictions were used
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score is 0.969, which is strongly predictive of pathogenicity. BayesDel score is 0.612, consistent with a damaging prediction. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a missense variant not near splice junctions. The REVEL score in particular provides strong in silico support. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.969 (strongly pathogenic).
- BayesDel score: 0.612 (damaging).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.969 strongly predicts pathogenicity. BayesDel score of 0.612 supports a damaging effect. While SpliceAI predicts no splicing impact (delta 0.01), the overall in silico profile supports a deleterious effect, opposite of BP4 requirements. Details ▾Hide ▴
Evidence considered
- REVEL 0.969: strongly pathogenic prediction.
- BayesDel 0.612: damaging prediction.
- SpliceAI 0.01: no splice impact
- but does not offset deleterious missense predictions.
Sources
BP7 BP7 applies to synonymous variants with no predicted splice impact. NM_000516.5:c.602G>A is a missense variant producing p.Arg201His, not a synonymous change. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- This is a missense variant (p.Arg201His)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.969. BayesDel score = 0.611857.
8 paper records listed. 4 cited in the classification.
Cited in the classification
-
PMID 15126527 ↗Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study.Lumbroso S et al. · 2004 MayLumbroso et al. conducted a systematic search for Gsα activating mutations in 113 patients with signs of McCune-Albright syndrome. The Arg201His mutation was identified in 34 of 49 mutation-positive patients (69%), making it the most common activating mutation. The mutation was detected in multiple tissue types including ovary, bone, liver, and blood.→ PS4 → PM5 Names this variant
Source detail
A mutation of arginine 201 in the Gsα protein was found in 49 of the 113 patients (43%), with a net preponderance of the substitution by histidine (n = 34) as opposed to cysteine (n = 15).
Location Abstract; Results para 1-4; Table 5
Context PCR-based enrichment method with EagI restriction digestion on DNA from 174 tissue samples across 113 patients
-
PMID 1594625 ↗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 et al. · 1992 Jun 1Schwindinger et al. identified the c.602G>A (p.Arg201His) mutation in a 53-year-old man with McCune-Albright syndrome. The mutation was detected in peripheral blood leukocytes and at low levels in skin, confirming somatic mosaicism. The authors discuss prior in vitro mutagenesis data showing that Arg201 substitutions reduce GTPase activity ~30-fold and constitutively activate adenylyl cyclase.→ PS4 → PM1 Names this variant
Source detail
This single-base substitution results in the replacement of arginine by histidine at position 201 of the mature Gsα protein.
Location Abstract; Results para 1-3; Discussion para 1-4
Context Denaturing gradient gel electrophoresis, allele-specific PCR, single-nucleotide primer extension on leukocyte and skin DNA from a single MAS patient
-
PMID 2549426 ↗GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.Landis et al. identified somatic mutations in the GNAS gene (then termed gsp oncogene) in a subset of human growth hormone-secreting pituitary tumors. The mutations replaced Arg201 with either Cys or His and Gln227 with Arg, resulting in inhibition of GTPase activity and constitutive activation of adenylyl cyclase. In vitro mutagenesis demonstrated that Arg201 substitutions reduce GTPase activity approximately 30-fold.→ PS3 Names this variant
Source detail
A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone.
Location Abstract
Context In vitro mutagenesis and GTPase activity assays on Gsα; functional characterization in S49 cyc- murine lymphoma cells (as cited by PMID:1594625)
-
PMID 26257060 ↗GNAS(R201H) and Kras(G12D) cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm.Taki et al. generated transgenic mice conditionally expressing GNAS R201H in the pancreas. GNAS R201H expression alone caused elevated cAMP levels, pancreatic ductal dilation, loss of acinar cells, and fibrosis. When combined with Kras G12D, GNAS R201H cooperatively promoted macroscopic cystic pancreatic tumors recapitulating human intraductal papillary mucinous neoplasm within 5 weeks.→ PS3 Names this variant
Source detail
The GNASR201H mutation results in constitutive activation of Gsα.
Location Abstract; Results and Discussion para 1-6; Figure 1-4
Context Transgenic mouse model (Tg(CAG-LSL-GNASR201H);Ptf1aCre/+); cAMP measurement, histopathology, Kaplan-Meier survival analysis
Other recorded publications
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PMID 28868010 ↗Clinical Benefit from Trametinib in a Patient with Appendiceal Adenocarcinoma with a GNAS R201H Mutation.Case report of a 53-year-old man with metastatic appendiceal adenocarcinoma harboring a GNAS R201H mutation identified by comprehensive genomic profiling. Treatment with the MEK inhibitor trametinib produced clinical benefit, suggesting that GNAS R201H-driven MAPK pathway activation can be therapeutically targeted.Names this variant
Quoted passage
We present a patient with a mucinous appendiceal adenocarcinoma and PMP refractory to several conventional chemotherapy agents who experienced clinical benefit from trametinib based on CGP results demonstrating a GNAS R201H mutation.
Introduction; Case Presentation; Discussion
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PMID 24855271 ↗Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.This is the ACMG/AMP 2015 standards and guidelines for interpretation of sequence variants. It provides the general classification framework and combination rules but does not discuss the specific GNAS c.602G>A variant.Does not name this variant
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PMID 26341786 ↗Neonatal McCune-Albright syndrome with systemic involvement: a case report.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
40 / 1,613,098 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
6 Pathogenic · 3 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/15934/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/20-57484421-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr20-58909366-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/20-58909366-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000516.5%3Ac.602G…
- OncoKB ↗www.oncokb.org/gene/GNAS/R201H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GNAS+c.602G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.4797e-05; MAF= 0.00248%, 40/1613098 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 6.75676e-05; MAF= 0.00676%, 2/29600 alleles, homozygotes = 0); grpmax FAF= 2.155e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59075e-05; MAF= 0.00159%, 4/251454 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.9226e-05; MAF= 0.00992%, 1/10078 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 15934)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.969. BayesDel score = 0.611857.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.