NM_002072.4:c.208G>T

GNAQ · NP_002063.2:p.(Glu70Ter) · NM_002072.4

GRCh37: chr9:80537190 C>A · GRCh38: chr9:77922274 C>A

Gene: GNAQ Transcript: NM_002072.4

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 moderate

Variant details

Gene

GNAQ

Transcript

NM_002072.4

Protein

NP_002063.2:p.(Glu70Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4
PS1	Not met	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. NM_002072.4:c.208G>T produces a premature stop codon (p.Glu70Ter). No alternative nucleotide change at codon 70 producing the same nonsense change with an established pathogenic classification has been identified.
PS2	Not met	PS2 requires a de novo occurrence with both maternity and paternity confirmed. No de novo data are available for NM_002072.4:c.208G>T.
PS3	Not met	PS3 requires variant-specific functional evidence from published experimental studies. No functional studies testing NM_002072.4:c.208G>T (p.Glu70Ter) were identified in the evidence brief, literature pass, or any reviewed publications. The OncoKB classification is 'Unknown Oncogenic Effect' and does not provide functional data for this variant.
PS4	Not met	PS4 requires a statistically significant enrichment of the variant in affected individuals versus controls. No case-control data or prevalence studies are available for NM_002072.4:c.208G>T.
PS5	Not met	PS5 requires a reputable source to have recently reported the variant as pathogenic but the evidence is not available for independent evaluation. NM_002072.4:c.208G>T is absent from ClinVar and has not been reported as pathogenic by any source.
PM1	Met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 requires a different missense change at the same amino acid residue that has been established as pathogenic. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a missense change. The pm5_candidates harvest found zero comparator variants at residue 70 in ClinVar. The well-characterized GNAQ pathogenic missense hotspots (Q209, R183) are at different residues and do not satisfy the same-codon requirement for PM5.	pm5_candidates
PM6	Not met	PM6 requires a de novo occurrence without confirmation of maternity and paternity. No de novo data are available for NM_002072.4:c.208G>T.
PP1	Not met	PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for NM_002072.4:c.208G>T.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a missense change.
PP3	N/A	PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene product. NM_002072.4:c.208G>T introduces a premature stop codon (p.Glu70Ter), which is inherently deleterious. The deleterious effect of a null variant is already captured by PVS1; applying PP3 to the same null effect would constitute double-counting. BayesDel score (0.588) and SpliceAI max delta (0.04) are noted but not applied under PP3 for a nonsense variant.
PP4	Not met	PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient phenotype or family history data are available for this case.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. NM_002072.4:c.208G>T is absent from ClinVar with no submissions from any submitter. No expert panel or clinical laboratory has classified this variant.	clinvar
BA1	Not met	BA1 requires an allele frequency >5% in any general population database. NM_002072.4:c.208G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada with an allele frequency of 0.0%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency greater than expected for the disorder (threshold >0.3% under non-VCEP generic ACMG). NM_002072.4:c.208G>T is absent from all queried population databases (allele frequency 0.0%).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No data indicating observation of NM_002072.4:c.208G>T in healthy adults are available. The variant is absent from all population databases.
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No functional studies testing NM_002072.4:c.208G>T were identified.
BS4	Not met	BS4 requires lack of segregation with disease in affected family members. No segregation data are available for NM_002072.4:c.208G>T.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants are a known disease mechanism. NM_002072.4:c.208G>T is itself a truncating (nonsense) variant, not a missense change, so BP1 is not applicable.
BP2	Not met	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. No phase data are available for NM_002072.4:c.208G>T.
BP4	N/A	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. NM_002072.4:c.208G>T is a nonsense variant introducing a premature stop codon, a clearly damaging molecular consequence. Computational prediction of benign impact is not meaningful for a null variant. SpliceAI predicts no splice impact (max delta 0.04), but this does not negate the damaging effect of the stop-gain itself.	spliceai
BP5	Not met	BP5 requires that the variant be found in a case with an alternate molecular basis for disease. No data indicating an alternate molecular cause in a patient carrying NM_002072.4:c.208G>T are available.
BP6	Not met	BP6 requires a reputable source to have reported the variant as benign. NM_002072.4:c.208G>T is absent from ClinVar with no classifications from any submitter.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a synonymous change.

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