NM_002072.4:c.208G>T (p.Glu70Ter) is a nonsense variant in exon 2 of GNAQ, introducing a premature termination codon predicted to trigger nonsense-mediated decay and truncating the protein before the GTPase domain. This qualifies as a null variant (PVS1, very strong) under the ClinGen SVI framework (PMC6185798).1 The variant is located within the Ras-like GTPase domain (residues 36-355), a critical functional domain for GNAQ GTP-binding and signaling activity. Truncation at codon 70 eliminates the entire GTPase domain (PM1, moderate). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, representing a large, diverse population cohort with allele frequency 0.0% (PM2, moderate).2 Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), one very strong criterion (PVS1) plus two moderate criteria (PM1, PM2) meets the threshold for Pathogenic classification.3 Caution is warranted: GNAQ germline loss-of-function disease mechanism is not established by an official ClinGen CSPEC/VCEP. The supporting literature is drawn predominantly from somatic cancer and mosaic cutaneous disorder contexts. A definitive germline tumor predisposition syndrome from GNAQ LoF has not been independently validated.
GNAQ
Final classification
Pathogenic
GNAQ c.208G>T · p.Glu70Ter
GNAQ
NM_002072.4:c.208G>T (p.Glu70Ter) is a nonsense variant in exon 2 of GNAQ, introducing a premature termination codon predicted to trigger nonsense-mediated decay and truncating the protein before the GTPase domain. This qualifies as a null variant (PVS1, very strong) under the ClinGen SVI framework (PMC6185798).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 moderate; combination = 1 very strong + 2 moderate, which maps to Pathogenic.
Classification rationale
PVS1PM1PM2
Pathogenic
GNAQ c.208G>T
PVS1 + PM1 + PM2
→
Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
generic_acmg_combination_rules
Gene diagram
· NM_002072.4 · variants mapped to exon structure
GNAQ
NM_002072.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
NM_002072.4:c.208G>T is a nonsense variant (p.Glu70Ter) in exon 2 of 7, producing a premature termination codon at amino acid 70 of 359. The truncation removes approximately 81% of the protein including the entire GTPase domain and is predicted to trigger nonsense-mediated decay. Under the ClinGen SVI PVS1 framework (PMC6185798), a null variant in a gene where loss of function is a known germline disease mechanism qualifies for PVS1 at very strong strength when NMD is predicted. GNAQ germline loss of function is supported by the literature as a disease mechanism, though the evidence base draws predominantly from somatic and mosaic disease contexts.
Nonsense variant c.208G>T introduces premature stop at codon 70 (p.Glu70Ter)Variant located in exon 2 of 7early truncation predicted to trigger NMD
✓
PM1
moderate
review
Pathogenic
The variant introduces a premature stop codon (p.Glu70Ter) within the Ras-like GTPase domain of GNAQ (residues 36-355), which is the critical functional domain responsible for GTP binding and hydrolysis. Truncation at codon 70 removes the entire GTPase domain and all downstream functional elements. Under generic ACMG/AMP, PM1 applies when a variant is located in a well-characterized critical functional domain without benign variation. The cancerhotspots.org database does not flag residue 70 as a statistically significant hotspot, but PM1 may be satisfied by domain-level characterization without requiring residue-level hotspot significance.
Premature stop at codon 70 located within the Ras-like GTPase domain (residues ~36-355)a well-characterized critical functional domainTruncation removes the entire GTPase domain and all downstream functional elements (G1-G5 boxes
✓
PM2
moderate
Pathogenic
NM_002072.4:c.208G>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), representing a large, diverse population cohort. Under generic ACMG/AMP, absence from population databases at an allele frequency below 0.1% supports a moderate level of evidence for pathogenicity (PM2).
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change, with the comparator variant previously established as pathogenic.
PS2
PS2 requires a de novo occurrence with both maternity and paternity confirmed.
PS3
PS3 requires variant-specific functional evidence from published experimental studies.
PS4
PS4 requires a statistically significant enrichment of the variant in affected individuals versus controls.
PM5
PM5 requires a different missense change at the same amino acid residue that has been established as pathogenic.
PM6
PM6 requires a de novo occurrence without confirmation of maternity and paternity.
PP1
PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP4
PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have recently reported the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >5% in any general population database.
BS1
BS1 requires an allele frequency greater than expected for the disorder (threshold >0.3% under non-VCEP generic ACMG).
BS2
BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing.
BS4
BS4 requires lack of segregation with disease in affected family members.
BP2
BP2 requires observation of the variant in trans with a pathogenic dominant variant, or in cis with a known pathogenic variant in a recessive gene.
BP5
BP5 requires that the variant be found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have reported the variant as benign.
N/A · 5
PP2 · PP3 · BP1 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.588046.
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links