Variant classification summary

NM_002072.5:c.627A>C

GNAQ · NP_002063.2:p.(Gln209His) · NM_002072.5

GRCh37: chr9:80409487 T>G · GRCh38: chr9:77794571 T>G

Gene: GNAQ Transcript: NM_002072.5

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM5 moderate PP5 supporting

Variant details

Gene

GNAQ

Transcript

NM_002072.5

Protein

NP_002063.2:p.(Gln209His)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The variant is located at codon 209 within the GTPase domain of GNAQ, a well-established functional hotspot (PM1).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).

3

A different pathogenic missense change at the same codon, p.Gln209Leu, has been established as a gain-of-function activating mutation in functional studies (PM5).

4

This variant has been reported as Pathogenic in ClinVar by two clinical laboratories (PP5).

5

Three moderate criteria (PM1, PM2, PM5) and one supporting criterion (PP5) are met, reaching the Likely Pathogenic threshold per ACMG/AMP 2015 generic combination rules (3 moderate criteria).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of 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	N/A	NM_002072.5:c.627A>C is a missense variant (p.Gln209His). It does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant with the same amino acid change (p.Gln209His) arising from a different nucleotide change has been identified.
PS2	N/A	No de novo data are available for this variant. Both maternity and paternity confirmation would be required.
PS3	Not met	No variant-specific functional data for c.627A>C (p.Gln209His) was identified in the literature. Functional studies have characterized other substitutions at codon 209 (p.Gln209Leu, p.Gln209Pro) as gain-of-function, but the exact variant has not been directly tested. Per PS3 calibration rules, domain-level inference from a single tested residue at the same codon without systematic range characterization does not satisfy variant-specific PS3 requirements.	PMID:23656586 oncokb
PS4	Not met	No case-control or cohort prevalence data are available to establish significantly increased prevalence of this variant in affected individuals compared with controls.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 generic framework (Richards et al., PMID:25741868). The same-codon pathogenic missense evidence is captured under PM5.	PMID:25741868
PM1	Met	The variant is located at codon 209 (p.Gln209His) within the GTPase domain of GNAQ, a well-established functional hotspot. Codon 209 is a statistically significant hotspot at cancerhotspots.org, and substitutions at this residue (p.Gln209Leu, p.Gln209Pro) are known activating mutations that disrupt GTP hydrolysis, leading to constitutive Gαq signaling.	PMID:23656586 oncokb
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant (allele frequency <0.1% threshold for non-VCEP assessment).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	p.Gln209His is a novel missense change at codon 209 where a different missense change, p.Gln209Leu (c.626A>T), has been established as pathogenic. p.Gln209Leu is a well-characterized gain-of-function mutation in uveal melanoma and was experimentally confirmed to activate MAPK signaling in functional studies (PMID:23656586).	PMID:23656586 oncokb
PM6	N/A	No de novo data are available for this variant.
PP1	Not met	No co-segregation data are available for this variant. No family studies have been reported.
PP2	Not assessed	HCI prior score is not available for GNAQ, and gene-level missense constraint data are insufficient to determine whether GNAQ has a low rate of benign missense variation.
PP3	Not met	Computational evidence is mixed and does not meet the multiple-lines threshold. REVEL score of 0.725 supports a deleterious effect, but BayesDel score of 0.164 does not reach the deleterious threshold (~0.27), and SpliceAI predicts no splicing impact (max delta score = 0.01).	revel bayesdel spliceai
PP4	Not met	No phenotype or family history data are available for this variant. Patient-specific clinical information is not present in the case materials.
PP5	Met	This variant has been reported as Pathogenic in ClinVar (Variation ID 1172601) by two clinical laboratories, though the evidence supporting the classification is not available for independent evaluation.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% allele frequency threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD. Does not meet the >0.3% allele frequency threshold for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adult controls with full penetrance expected.
BS3	Not met	No well-established functional studies show a benign effect. Functional data from related substitutions at codon 209 (p.Gln209Leu) demonstrate gain-of-function activation of MAPK signaling, consistent with a damaging rather than benign effect.	PMID:23656586
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	GNAQ disease mechanism includes gain-of-function missense variants (e.g., p.Gln209Leu, p.Arg183Gln). The gene is not limited to a truncating-only disease mechanism.	PMID:23656586
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Not met	Computational evidence does not support a benign effect. REVEL score of 0.725 is in the deleterious range, and SpliceAI shows no splicing impact. The evidence does not meet the multiple-lines-of-benign threshold.	revel bayesdel spliceai
BP5	Not met	No evidence is available that this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	This variant is not reported as benign by any reputable source. ClinVar reports it as Pathogenic.	clinvar
BP7	N/A	This is a missense variant (c.627A>C, p.Gln209His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

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