About GNAQ
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GNAQ c.548G>A, p.(Arg183Gln)
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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
Two independent publications directly tested NM_002072.5:c.548G>A (p.Arg183Gln) in functional assays and both demonstrate a gain-of-function activating effect. Shirley et al. (PMID:23656586) showed p.Arg183Gln activates ERK phosphorylation and SRE promoter activity in HEK293T cells. Yu et al. (PMID:24882516) showed GqR183Q potently activates YAP/TAZ in HEK293A cells. The functional effect is unequivocal and confirmed across independent laboratories and assay types.
PM1Moderate
PM1 · moderate
The variant is located at Arg183, a residue within the GTP-binding pocket (switch I domain) of Gαq, a critical and well-established functional domain. This position is a statistically significant cancer hotspot (cancerhotspots.org), is reported 59 times in COSMIC, and is completely devoid of benign variation in gnomAD. The domain is characterized in PMID:23656586 and PMID:24882516 as essential for GTP hydrolysis and protein inactivation.
PM2Moderate
PM2 · moderate
The variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency of 0% meets the PM2 threshold (<0.1%) for a rare variant absent from population controls.
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect: REVEL score 0.855 (deleterious, >0.5 threshold) and BayesDel score 0.476 (>0.27 add threshold). SpliceAI predicts no splicing impact (max delta 0.04), consistent with a missense effect rather than splicing alteration.
PP5Supporting
PP5 · supporting
This variant has been reported in ClinVar as Pathogenic by 8 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (ClinVar ID: 50853). While most submissions pertain to somatic conditions, one clinical testing laboratory (Greenwood Genetic Center, SCV005873972) has classified it as Pathogenic for GNAQ-related disorder in a germline context. Multiple reputable clinical sources support 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, PM1 moderate, PM2 moderate, PP3 supporting, PP5 supporting; combination = 1 strong + 2 moderate + 2 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
9 reported laboratory submissions
8 Pathogenic · 1 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: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
59 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54106047, n = 59 times).
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: 5 met · 18 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PS3 (strong): Two independent publications (PMID:23656586, PMID:24882516) directly tested NM_002072.5:c.548G>A (p.Arg183Gln) and demonstrated gain-of-function activation of downstream signaling pathways (ERK activation, YAP/TAZ activation) in cell-based assays.
PM1 (moderate): The variant is located at Arg183 in the GTP-binding pocket/switch I domain of Gαq, a critical functional domain essential for GTP hydrolysis. This residue is a statistically significant cancer hotspot (cancerhotspots.org) with 59 COSMIC entries and no benign variation in gnomAD.
PM2 (moderate): The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the <0.1% threshold for rarity.
PP3 (supporting): Multiple in silico predictors support a deleterious effect: REVEL score 0.855 and BayesDel score 0.476.
PP5 (supporting): This variant has been reported as Pathogenic by 8 clinical laboratories and Likely pathogenic by 1 clinical laboratory in ClinVar (Variation ID: 50853).
Classification: PATHOGENIC. The combination of 1 Strong (PS3), 2 Moderate (PM1, PM2), and 2 Supporting (PP3, PP5) criteria satisfies the ACMG/AMP 2015 pathogenic threshold (1 Strong + 2 Moderate + 2 Supporting → Pathogenic).
Note: This variant is a well-characterized somatic gain-of-function mutation causing Sturge-Weber syndrome and port-wine stains in mosaic state (PMID:23656586). Germline classification is supported by ClinVar submissions and functional evidence, though most clinical observations are in somatic rather than constitutional contexts.
No criteria match.
Met · 5
PS3 StrongTwo independent publications directly tested NM_002072.5:c.548G>A (p.Arg183Gln) in functional assays and both demonstrate a gain-of-function activating effect. Shirley et al. (PMID:23656586) showed p.Arg183Gln activates ERK phosphorylation and SRE promoter activity in HEK293T cells. Yu et al. (PMID:24882516) showed GqR183Q potently activates YAP/TAZ in HEK293A cells. The functional effect is unequivocal and confirmed across independent laboratories and assay types. Details ▾Hide ▴
Evidence considered
- PMID:23656586: GNAQ p.Arg183Gln activates ERK (Western blot) and SRE promoter (luciferase reporter) in HEK293T cells
- confirmed gain-of-function.
- PMID:24882516: GqR183Q potently activates YAP/TAZ (dephosphorylation
- nuclear localization) in HEK293A cells.
- OncoKB: Likely Oncogenic
- Likely Gain-of-function.
Sources
PM1 ModerateThe variant is located at Arg183, a residue within the GTP-binding pocket (switch I domain) of Gαq, a critical and well-established functional domain. This position is a statistically significant cancer hotspot (cancerhotspots.org), is reported 59 times in COSMIC, and is completely devoid of benign variation in gnomAD. The domain is characterized in PMID:23656586 and PMID:24882516 as essential for GTP hydrolysis and protein inactivation. Details ▾Hide ▴
Evidence considered
- Arg183 lies in the GTP-binding pocket / switch I domain
- critical for GTP hydrolysis.
- Statistically significant hotspot at cancerhotspots.org.
- Reported 59 times in COSMIC (COSV54106047).
- Absent from gnomAD v2.1 and v4.1 (no benign variation at this residue).
Sources
PM2 ModerateThe variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency of 0% meets the PM2 threshold (<0.1%) for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.855 (deleterious, >0.5 threshold) and BayesDel score 0.476 (>0.27 add threshold). SpliceAI predicts no splicing impact (max delta 0.04), consistent with a missense effect rather than splicing alteration. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.855 (deleterious).
- BayesDel score: 0.476 (deleterious).
- SpliceAI max delta: 0.04 (no predicted splicing impact).
Still missing
- HCI prior not available for GNAQ.
Sources
PP5 SupportingThis variant has been reported in ClinVar as Pathogenic by 8 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (ClinVar ID: 50853). While most submissions pertain to somatic conditions, one clinical testing laboratory (Greenwood Genetic Center, SCV005873972) has classified it as Pathogenic for GNAQ-related disorder in a germline context. Multiple reputable clinical sources support pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic (8 clinical labs)
- Likely pathogenic (1 clinical lab).
- At least one germline clinical testing submission classifies as Pathogenic (SCV005873972).
Still missing
- Most ClinVar submissions are for somatic rather than germline origin.
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo observation (maternity and paternity confirmed) has been reported for NM_002072.5:c.548G>A in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No de novo reports found in literature or ClinVar submissions.
Still missing
- No de novo data available for this variant.
PS4 No germline case-control data or statistically significant enrichment in affected individuals versus controls has been demonstrated for this variant. Reported observations are predominantly somatic mosaic (Sturge-Weber syndrome, port-wine stains) and do not satisfy germline PS4 requirements. Details ▾Hide ▴
Evidence considered
- Variant reported in multiple somatic mosaic conditions (Sturge-Weber syndrome
- capillary malformations)
- no germline case-control data available.
Still missing
- No germline case-control studies available.
Sources
PM5 No different pathogenic missense variant at residue Arg183 was identified in ClinVar for PM5 comparison. Automatic PM5 candidate harvesting could not identify a same-residue comparator with established pathogenicity. Details ▾Hide ▴
Evidence considered
- No same-residue ClinVar comparator identified.
Still missing
- No established pathogenic comparator at Arg183 in ClinVar.
Sources
pm5_candidates
PM6 No de novo observation with confirmed maternity and paternity has been reported for NM_002072.5:c.548G>A. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo data available.
PP1 No co-segregation data with disease in multiple affected family members has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation studies available.
PP2 GNAQ is not established as a gene in which missense variants are a common mechanism of germline disease. The known pathogenic mechanism for this variant is gain-of-function in somatic mosaicism; there is no evidence that missense variants in GNAQ represent a prevalent germline disease mechanism. Details ▾Hide ▴
Evidence considered
- GNAQ germline disease mechanism not established as predominantly missense-mediated.
Still missing
- Limited germline disease association data for GNAQ.
PP4 No specific germline phenotype data or detailed clinical information for individual patients harboring this variant in germline context is available. Reported phenotypes are somatic mosaic conditions (Sturge-Weber syndrome, port-wine stains). Details ▾Hide ▴
Evidence considered
- Reported phenotypes are predominantly somatic (Sturge-Weber syndrome
- capillary malformations).
Still missing
- No detailed germline phenotype data available.
Sources
BA1 The variant is absent from gnomAD (allele frequency 0%). BA1 requires allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0% across all gnomAD datasets.
Sources
BS1 The variant is absent from gnomAD (allele frequency 0%). BS1 requires allele frequency >0.3% in population databases. Details ▾Hide ▴
BS2 No evidence that this variant has been observed in healthy adults in a germline context. The variant is absent from population databases. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no observation in healthy adults.
Sources
BS3 Functional studies (PMID:23656586, PMID:24882516) demonstrate a gain-of-function activating effect, not a benign effect. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- Two independent studies demonstrate gain-of-function activation of downstream signaling (ERK
- YAP/TAZ)
- contradicting a benign interpretation.
Sources
BS4 No evidence of non-segregation with disease in affected family members has been reported. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
Still missing
- No family segregation data.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. GNAQ germline disease is not established as primarily caused by loss-of-function truncating variants; the known pathogenic mechanism for this variant is gain-of-function. Details ▾Hide ▴
Evidence considered
- GNAQ pathogenic mechanism for this variant is gain-of-function
- not loss-of-function.
Sources
BP2 No evidence that this variant has been observed in trans with a known pathogenic variant in GNAQ. Details ▾Hide ▴
Evidence considered
- No observations in trans with a pathogenic variant.
BP4 Multiple in silico predictors support a deleterious effect (REVEL 0.855, BayesDel 0.476), contradicting a benign interpretation. BP4 requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL (0.855) and BayesDel (0.476) predict deleterious effect
- not benign.
Sources
revelbayesdel
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis reported in cases with this variant.
BP6 No reputable source reports this variant as benign. ClinVar classification is Pathogenic/Likely pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar reports Pathogenic (8 labs) and Likely pathogenic (1 lab)
- no benign classifications.
Sources
BP7 BP7 applies to synonymous variants with no predicted splicing impact. NM_002072.5:c.548G>A is a missense variant (p.Arg183Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Arg183Gln) does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework does not apply. Details ▾Hide ▴
Evidence considered
- Variant class is missense substitution
- PVS1 reserved for null variants.
Sources
PS1 N/ANo prior evidence that the exact same amino acid change (p.Arg183Gln) has been established as pathogenic via a different nucleotide change at this position. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change producing p.Arg183Gln identified.
PS5 N/ANo different pathogenic missense variant at the same residue (Arg183) has been identified as a comparator. PS5 requires an established pathogenic variant at the same position via a different nucleotide change. Details ▾Hide ▴
Evidence considered
- No alternate pathogenic missense at Arg183 identified.
Identifiers
- Gene
- GNAQ
- Transcript
- NM_002072.5
- Coding (HGVS c.)
- NM_002072.5:c.548G>A
- Protein (HGVS p.)
- NP_002063.2:p.(Arg183Gln)
- GRCh38
- chr9:77797577 C>T
- GRCh37
- chr9:80412493 C>T
- ClinVar
- 50853
- COSMIC
- COSV54106047
Gene diagram
Every interpreted variant in GNAQ, mapped onto the exon structure of NM_002072.5. Select a row to find it on the plot.
GNAQNM_002072.5
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 GNAQ
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.855
- BayesDel
- 0.476
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.855 (deleterious, >0.5 threshold) and BayesDel score 0.476 (>0.27 add threshold). SpliceAI predicts no splicing impact (max delta 0.04), consistent with a missense effect rather than splicing alteration. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.855 (deleterious).
- BayesDel score: 0.476 (deleterious).
- SpliceAI max delta: 0.04 (no predicted splicing impact).
Still missing
- HCI prior not available for GNAQ.
Sources
BP4 Multiple in silico predictors support a deleterious effect (REVEL 0.855, BayesDel 0.476), contradicting a benign interpretation. BP4 requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL (0.855) and BayesDel (0.476) predict deleterious effect
- not benign.
Sources
revelbayesdel
BP7 BP7 applies to synonymous variants with no predicted splicing impact. NM_002072.5:c.548G>A is a missense variant (p.Arg183Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.855. BayesDel score = 0.47592.
6 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 23656586 ↗Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.Shirley MD et al. · 2013 May 23NM_002072.5:c.548G>A (p.Arg183Gln) was directly identified as the causal somatic mosaic mutation in Sturge-Weber syndrome and nonsyndromic port-wine stains. Functional assays in HEK293T cells demonstrated that GNAQ p.Arg183Gln activates ERK phosphorylation and SRE promoter activity (luciferase reporter), confirming a gain-of-function effect. Activation by p.Arg183Gln was modest compared to p.Gln209Leu and did not activate p38 or JNK.→ PS3 → PM1 Names this variant
Source detail
cells transfected with GNAQ p.Gln209Leu or GNAQ p.Arg183Gln, as compared with cells transfected with nonmutant GNAQ, showed significant activation of extracellular signal-regulated kinase (ERK) (P<0.05)
Location Results; Figures 2A-F
Context HEK293T cells; Western blotting for ERK, p38, JNK; luciferase reporter assay (pSRE-Luc); site-directed mutagenesis of GNAQ
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PMID 24882516 ↗Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.Yu FX et al. · 2014 Jun 16GqR183Q was shown to potently activate YAP/TAZ in HEK293A cells, demonstrated by YAP dephosphorylation on phos-tag gels and increased YAP/TAZ nuclear localization. The study established YAP as a key downstream effector of oncogenic Gq/11 mutants in uveal melanoma and confirmed that the R183Q mutation, like Q209L, produces a constitutively active Gαq.→ PS3 Names this variant
Source detail
GqR183Q also potently activated YAP
Location Figure 1A; Figure S1A-C; Discussion paragraph 7
Context HEK293A cells; phos-tag Western blot for YAP phosphorylation; immunofluorescence for YAP/TAZ subcellular localization
Other recorded publications
-
PMID 22236444 ↗Genetic and molecular characterization of uveal melanoma cell lines.Identified GNAQ R183Q mutation in uveal melanoma cell line UPMM1 during systematic characterization of 19 uveal melanoma cell lines. Mutations at codon 183 (R183Q) occurred less frequently than Q209 mutations. The paper primarily reports cell line authentication and mutation status; no direct functional assay of R183Q was performed.Names this variant
Quoted passage
Mutations at codon 183 (R183Q) were found in GNAQ in one cell line (UPMM1)
Results paragraph 2
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PMID 26619011 ↗Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Describes a statistical algorithm (HotMAPS) for detecting significantly mutated residues across cancer types. Discusses mutational hotspots at the gene and pathway level but does not mention the specific NM_002072.5:c.548G>A variant or GNAQ R183 individually.Does not name this variant
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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.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methods and consensus recommendation paper that does not discuss any specific variant, gene, or disease.Does not name this variant
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PMID 39434542 ↗Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism.Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism by the Brain Malformations Variant Curation Expert Panel. This is a methodological paper proposing modified ACMG/AMP rules for somatic mosaic disorders; does not discuss the specific GNAQ c.548G>A variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
8 Pathogenic · 1 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/50853/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-80412493-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-77797577-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-77797577-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002072.5%3Ac.548G…
- OncoKB ↗www.oncokb.org/gene/GNAQ/R183Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121976152
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 50853)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.855. BayesDel score = 0.47592.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54106047, n = 59 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.