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).1 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).2 The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).3 Other pathogenic missense changes at the same residue (Gln209Pro, Gln209Arg, Gln209His) have been established as pathogenic (PM5).4 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).5 Multiple in silico tools predict a deleterious effect: REVEL score 0.936, BayesDel consistent with damaging prediction (PP3).6 ClinVar classifies this variant as Pathogenic (variation ID 375955, one clinical laboratory with criteria provided) (PP5).7 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.8
GNAQ
Final classification
Pathogenic
GNAQ c.626A>T · p.Gln209Leu
GNAQ
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).
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.
Classification rationale
PS3PM1PM2PM5PP2PP3PP5
Pathogenic
GNAQ c.626A>T
PS3 + PM1 + PM2 + PM5 + PP2 + PP3 + PP5
→
Pathogenic
6
revelbayesdel
8
generic_acmg_combination_rules
Gene diagram
· NM_002072.5 · variants mapped to exon structure
GNAQ
NM_002072.5
Fetching transcript structure from UCSC…
Applied criteria · 7 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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
Oncogenic
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
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54105914, n = 346 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · 6 PMIDs triaged · 6 high-priority
6papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
1328859 ↗
functional
Mutated alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells.
The discovery of mutated, GTPase-deficient alpha subunits of Gs or Gi2 in certain human endocrine tumors has suggested that heterotrimeric G proteins play a role in the oncogenic process. Expression of these altered forms of G alpha s or G alpha i2 proteins in rodent fibroblasts activates or inhibits endogenous adenylyl cyclase, respectively, and causes certain alterations in cell growth. However,
BS3PM1PS3
19078957 ↗
functional
Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown. Here w
BS3PM1PS3
19718445 ↗
functional
Mutational profile of GNAQQ209 in human tumors.
Frequent somatic mutations have recently been identified in the ras-like domain of the heterotrimeric G protein alpha-subunit (GNAQ) in blue naevi 83%, malignant blue naevi (50%) and ocular melanoma of the uvea (46%). The mutations exclusively affect codon 209 and result in GNAQ constitutive activation which, in turn, acts as a dominant oncogene. To assess if the mutations are present in other tum
BS3PM1PS3
21083380 ↗
functional
Mutations in GNA11 in uveal melanoma.
Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282
BS3PM1PS3
31336681 ↗
functional
GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma.
Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. Here, we report the results of GNAQ/GNA11 mutation analys
BS3PM1PS3
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
Sources & reference links