About GNAQ
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GNAQ c.626A>T, p.(Gln209Leu)
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.
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Criteria may be applied incorrectly, sources may be misread, and a
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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
Multiple well-established in vitro and in vivo functional studies from independent groups demonstrate that the Gln209Leu substitution in GNAQ causes GTPase deficiency, constitutive activation of downstream signaling, and malignant transformation. This gain-of-function effect is a well-replicated finding constituting strong functional evidence of a damaging effect.
PM1Moderate
PM1 · moderate
Codon 209 is a well-established mutational hotspot in GNAQ, located in the GTPase domain. Cancer Hotspots confirms statistically significant clustering at this residue. Multiple publications identify codon 209 as one of two major GNAQ hotspot loci (along with codon 183).
PM2Moderate
PM2 · moderate
NM_002072.5:c.626A>T is absent from all large population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Allele frequency is well below the 0.1% threshold for PM2.
PM5Moderate
PM5 · moderate
Other pathogenic missense variants have been established at the same amino acid residue (Gln209): p.Gln209Pro (Q209P), p.Gln209Arg (Q209R), and p.Gln209His (Q209H). PMID:19718445 reports multiple substitutions at codon 209 as constitutively activating. PMID:31336681 specifically identifies Q209R as pathogenic.
PP2Supporting
PP2 · supporting
GNAQ has a low rate of benign missense variation and missense variants at key residues (codons 183 and 209) are the established mechanism of disease. The complete absence of this variant from gnomAD is consistent with high missense constraint.
PP3Supporting
PP3 · supporting
REVEL score of 0.936 strongly predicts a deleterious effect. BayesDel (noAF) score is also consistent with a damaging prediction. SpliceAI predicts no splicing impact (max delta 0.03), but this does not contradict the pathogenicity of the missense change.
PP5Supporting
PP5 · supporting
ClinVar reports NM_002072.5:c.626A>T (p.Gln209Leu) as Pathogenic (variation ID 375955). One clinical laboratory (Clinical Genomics Laboratory, Washington University in St. Louis) submitted this classification with criteria provided.
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, PM5 moderate, PP2 supporting, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
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
346 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54105914, n = 346 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.
29 criteria with recorded statuses: 7 met · 14 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002072.5:c.626A>T (p.Gln209Leu) is a well-characterized gain-of-function missense variant in GNAQ. Multiple independent functional studies demonstrate GTPase deficiency, constitutive activation of downstream MAPK/ERK signaling, and malignant transformation (PS3_strong).
The variant is located at codon 209, a statistically significant mutational hotspot in the GTPase domain of GNAQ where multiple pathogenic missense substitutions (Q209L, Q209P, Q209H, Q209R) cluster (PM1).
The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).
Other pathogenic missense changes at the same residue (Gln209Pro, Gln209Arg, Gln209His) have been established as pathogenic (PM5).
GNAQ has a low rate of benign missense variation and missense variants at residues 183 and 209 are the established gain-of-function disease mechanism (PP2).
Multiple in silico tools predict a deleterious effect: REVEL score 0.936, BayesDel consistent with damaging prediction (PP3).
ClinVar classifies this variant as Pathogenic (variation ID 375955, one clinical laboratory with criteria provided) (PP5).
Applying the ACMG/AMP 2015 generic combination rules: 1 Strong (PS3) + 3 Moderate (PM1, PM2, PM5) + 3 Supporting (PP2, PP3, PP5) satisfies the threshold for Pathogenic.
No criteria match.
Met · 7
PS3 StrongMultiple well-established in vitro and in vivo functional studies from independent groups demonstrate that the Gln209Leu substitution in GNAQ causes GTPase deficiency, constitutive activation of downstream signaling, and malignant transformation. This gain-of-function effect is a well-replicated finding constituting strong functional evidence of a damaging effect. Details ▾Hide ▴
Evidence considered
- PMID:1328859: Demonstrated that Q209L Gαq is GTPase-deficient and induces malignant transformation in NIH 3T3 cells.
- PMID:19078957: Identified Q209L as a frequent activating somatic mutation in uveal melanoma (~50%).
- PMID:19718445: Confirmed GNAQ codon 209 mutations cause constitutive activation across multiple tumor types.
Sources
PM1 ModerateCodon 209 is a well-established mutational hotspot in GNAQ, located in the GTPase domain. Cancer Hotspots confirms statistically significant clustering at this residue. Multiple publications identify codon 209 as one of two major GNAQ hotspot loci (along with codon 183). Details ▾Hide ▴
Evidence considered
- Cancer Hotspots identifies codon 209 as a statistically significant hotspot.
- PMID:19078957 and PMID:19718445 confirm codon 209 as a recurrently mutated residue in human neoplasia.
- Multiple pathogenic missense variants cluster at this residue (Q209L
- Q209P
- Q209H
- Q209R).
Sources
PM2 ModerateNM_002072.5:c.626A>T is absent from all large population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Allele frequency is well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=0).
- Absent from gnomAD v4.1 (AF=0).
- Absent from gnomAD-Canada v1.0.
Sources
PM5 ModerateOther pathogenic missense variants have been established at the same amino acid residue (Gln209): p.Gln209Pro (Q209P), p.Gln209Arg (Q209R), and p.Gln209His (Q209H). PMID:19718445 reports multiple substitutions at codon 209 as constitutively activating. PMID:31336681 specifically identifies Q209R as pathogenic. Details ▾Hide ▴
Evidence considered
- PMID:19718445: Multiple mutations at codon 209 cause constitutive GNAQ activation.
- PMID:31336681: Q209R identified as highly specific pathogenic variant in circumscribed choroidal hemangioma.
- Q209P and Q209H are known pathogenic alternate substitutions at the same residue.
Sources
PP2 SupportingGNAQ has a low rate of benign missense variation and missense variants at key residues (codons 183 and 209) are the established mechanism of disease. The complete absence of this variant from gnomAD is consistent with high missense constraint. Details ▾Hide ▴
Evidence considered
- GNAQ missense variants at residues 183 and 209 are the known gain-of-function disease mechanism.
- The variant is absent from large population databases
- consistent with purifying selection against missense changes at functional residues.
Sources
PP3 SupportingREVEL score of 0.936 strongly predicts a deleterious effect. BayesDel (noAF) score is also consistent with a damaging prediction. SpliceAI predicts no splicing impact (max delta 0.03), but this does not contradict the pathogenicity of the missense change. Details ▾Hide ▴
Evidence considered
- REVEL: 0.936 (strongly deleterious).
- BayesDel (noAF): 0.363 (consistent with deleterious).
- SpliceAI: max delta 0.03 (no splicing impact).
Sources
PP5 SupportingClinVar reports NM_002072.5:c.626A>T (p.Gln209Leu) as Pathogenic (variation ID 375955). One clinical laboratory (Clinical Genomics Laboratory, Washington University in St. Louis) submitted this classification with criteria provided. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 375955: Pathogenic
- criteria provided
- single submitter.
- Submitter: Clinical Genomics Laboratory
- Washington University in St. Louis.
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No alternative nucleotide change producing the same Gln209Leu substitution with established pathogenicity has been identified. The known pathogenic Gln209Leu change is this variant itself (c.626A>T). Details ▾Hide ▴
Evidence considered
- The Q209L substitution is known to be pathogenic
- but no alternative nucleotide change (e.g.
- c.626A>C or c.627G>T producing Q209L) has been independently established as pathogenic.
PS2 No confirmed de novo germline occurrence of NM_002072.5:c.626A>T has been reported. This variant is predominantly observed as a somatic mutation in tumor tissues. Details ▾Hide ▴
Evidence considered
- No de novo germline observation found in literature or databases. GNAQ codon 209 mutations are characteristically somatic.
Sources
25741868
PS4 The variant is absent from population databases (gnomAD) and highly prevalent in somatic tumor cohorts (COSMIC n=346), but no formal germline case-control study is available. Somatic tumor frequency does not satisfy PS4 for germline variant interpretation. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (population controls).
- COSMIC reports 346 somatic observations
- but somatic enrichment does not fulfill germline PS4 requirements.
Still missing
- No germline case-control study available to calculate odds ratio.
Sources
PM6 No de novo occurrence (germline or mosaic) of NM_002072.5:c.626A>T with unconfirmed parentage has been reported. This variant is predominantly somatic. Details ▾Hide ▴
Evidence considered
- No de novo observation in the available literature.
PP1 No co-segregation data are available. NM_002072.5:c.626A>T is predominantly a somatic variant and does not segregate in families. Details ▾Hide ▴
Evidence considered
- No familial cases with segregation data identified.
BA1 NM_002072.5:c.626A>T is absent from gnomAD v2.1 and v4.1. Allele frequency is 0%, far below the 5% BA1 threshold. Details ▾Hide ▴
BS1 NM_002072.5:c.626A>T is absent from gnomAD. Allele frequency (0%) is far below the 0.3% BS1 threshold. BS1 requires the variant to be more common than expected for the disorder. Details ▾Hide ▴
Evidence considered
- Absent from population databases
- AF=0
- far below BS1 threshold.
Sources
BS2 No observation of NM_002072.5:c.626A>T in healthy adult individuals has been reported. The variant is absent from population databases and has not been documented in asymptomatic carriers. Details ▾Hide ▴
Evidence considered
- Not observed in healthy controls.
BS3 Well-established functional studies universally demonstrate a gain-of-function, damaging effect for the Gln209Leu substitution (GTPase deficiency, constitutive signaling, transformation). BS3 requires well-established studies showing no damaging effect, which is the opposite of the available evidence. Details ▾Hide ▴
Evidence considered
- All functional evidence demonstrates gain-of-function (damaging)
- not benign effect.
- BS3 cannot be applied when functional assays show a pathogenic mechanism.
Sources
BP1 GNAQ disease is driven by gain-of-function missense variants, not truncating loss-of-function variants. BP1 supports benignity when a missense variant occurs in a gene where primarily truncating variants cause disease; because GNAQ's mechanism is missense gain-of-function, BP1 does not apply. Details ▾Hide ▴
Evidence considered
- GNAQ pathogenic mechanism is gain-of-function via missense mutations
- not truncating loss-of-function.
- BP1 is not met because the gene's disease mechanism is missense-based.
Sources
BP2 NM_002072.5:c.626A>T has not been observed in trans with a pathogenic variant in a dominant disorder or in cis with a known pathogenic GNAQ variant. Details ▾Hide ▴
Evidence considered
- No trans or cis observations with other pathogenic variants.
BP4 REVEL score of 0.936 strongly predicts a deleterious effect, directly contradicting the BP4 requirement of multiple lines of computational evidence suggesting no impact. BayesDel is also consistent with a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.936 (strongly pathogenic prediction).
- BayesDel (noAF): consistent with deleterious effect.
- Computational evidence uniformly supports pathogenicity
- not benignity.
Sources
revelbayesdel
BP5 No alternate molecular basis for disease has been identified in any case carrying NM_002072.5:c.626A>T. Details ▾Hide ▴
Evidence considered
- No cases reported where an alternate molecular cause was found.
BP6 ClinVar classifies NM_002072.5:c.626A>T as Pathogenic, not benign. No reputable source reports this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic. No benign classification from any submitter.
Sources
Not assessed · 1 · no assessment recorded
PP4 No patient phenotype or clinical history was provided with this case. PP4 requires evaluation of whether the patient's phenotype is highly specific for GNAQ-related disease. Details ▾Hide ▴
Evidence considered
- Insufficient clinical information to assess phenotypic specificity.
Still missing
- Patient phenotype information is required to evaluate PP4.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002072.5:c.626A>T is a missense variant (p.Gln209Leu), not a null variant (nonsense, frameshift, or canonical +/-1,2 splice site change). The generic PVS1 framework (PMC6185798) does not apply to non-null variants. GNAQ disease is driven by gain-of-function missense mutations, not loss-of-function. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PM3 N/ARecessive disorder criterion; GNAQ-associated disease follows a dominant/somatic mosaic pattern. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length change criterion; variant is a substitution. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ALack of segregation analysis is not applicable to GNAQ codon 209 variants because they are predominantly somatic and do not segregate in families. There is no familial disease context in which to evaluate BS4. Details ▾Hide ▴
Evidence considered
- No familial disease context exists for segregation analysis.
BP3 N/AIn-frame deletion/insertion criterion; variant is a substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_002072.5:c.626A>T is a missense variant (p.Gln209Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
PS5 N/APS5 is not defined in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868). Only PP5 (supporting strength) exists for evidence that a reputable source reports the variant as pathogenic without independent verification. Details ▾Hide ▴
Evidence considered
- PS5 is not a recognized ACMG/AMP criterion.
Identifiers
- Gene
- GNAQ
- Transcript
- NM_002072.5
- Coding (HGVS c.)
- NM_002072.5:c.626A>T
- Protein (HGVS p.)
- NP_002063.2:p.(Gln209Leu)
- GRCh38
- chr9:77794572 T>A
- GRCh37
- chr9:80409488 T>A
- ClinVar
- 375955
- COSMIC
- COSV54105914
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.936
- BayesDel
- 0.363
How the predictions were used
PP3 SupportingREVEL score of 0.936 strongly predicts a deleterious effect. BayesDel (noAF) score is also consistent with a damaging prediction. SpliceAI predicts no splicing impact (max delta 0.03), but this does not contradict the pathogenicity of the missense change. Details ▾Hide ▴
Evidence considered
- REVEL: 0.936 (strongly deleterious).
- BayesDel (noAF): 0.363 (consistent with deleterious).
- SpliceAI: max delta 0.03 (no splicing impact).
Sources
BP4 REVEL score of 0.936 strongly predicts a deleterious effect, directly contradicting the BP4 requirement of multiple lines of computational evidence suggesting no impact. BayesDel is also consistent with a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.936 (strongly pathogenic prediction).
- BayesDel (noAF): consistent with deleterious effect.
- Computational evidence uniformly supports pathogenicity
- not benignity.
Sources
revelbayesdel
BP7 N/ANM_002072.5:c.626A>T is a missense variant (p.Gln209Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.936. BayesDel score = 0.363052.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 1328859 ↗Mutated alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells.No paper-specific finding is recorded.
-
PMID 19078957 ↗Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.No paper-specific finding is recorded.
-
PMID 19718445 ↗Mutational profile of GNAQQ209 in human tumors.No paper-specific finding is recorded.
-
PMID 21083380 ↗Mutations in GNA11 in uveal melanoma.No paper-specific finding is recorded.
-
PMID 31336681 ↗GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma.No paper-specific finding is recorded.
-
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. · 2015No paper-specific finding is recorded.
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 0.030
Open source ↗
ClinVar
1 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/375955/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-80409488-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-77794572-T-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002072.5%3Ac.626A…
- OncoKB ↗www.oncokb.org/gene/GNAQ/Q209L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121976019
- 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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 375955)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.936. BayesDel score = 0.363052.
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 previously been reported in somatic cancers (COSMIC; COSV54105914, n = 346 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.