Variant classification summary

NM_002072.5:c.626A>T

GNAQ · NP_002063.2:p.(Gln209Leu) · NM_002072.5

GRCh37: chr9:80409488 T>A · GRCh38: chr9:77794572 T>A

Gene: GNAQ Transcript: NM_002072.5

Final call

Pathogenic

PS3 strong PM1 moderate PM2 moderate PM5 moderate PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

GNAQ

Transcript

NM_002072.5

Protein

NP_002063.2:p.(Gln209Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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).

3

The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).

4

Other pathogenic missense changes at the same residue (Gln209Pro, Gln209Arg, Gln209His) have been established as pathogenic (PM5).

5

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).

6

Multiple in silico tools predict a deleterious effect: REVEL score 0.936, BayesDel consistent with damaging prediction (PP3).

7

ClinVar classifies this variant as Pathogenic (variation ID 375955, one clinical laboratory with criteria provided) (PP5).

8

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.

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	N/A	NM_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.	pvs1_generic_framework
PS1	Not met	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).
PS2	Not met	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.
PS3	Met	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.	PMID:1328859 PMID:19078957 PMID:19718445
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 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.
PM1	Met	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).	PMID:19078957 PMID:19718445
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Met	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.	PMID:19718445 PMID:31336681
PM6	Not met	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.
PP1	Not met	No co-segregation data are available. NM_002072.5:c.626A>T is predominantly a somatic variant and does not segregate in families.
PP2	Met	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.	gnomad_v2 gnomad_v4
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.
BS3	Not met	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.	PMID:1328859 PMID:19078957 PMID:19718445
BS4	N/A	Lack 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.
BP1	Not met	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.	PMID:19078957 PMID:19718445
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel
BP5	Not met	No alternate molecular basis for disease has been identified in any case carrying NM_002072.5:c.626A>T.
BP6	Not met	ClinVar classifies NM_002072.5:c.626A>T as Pathogenic, not benign. No reputable source reports this variant as benign.	clinvar
BP7	N/A	NM_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.
BP3	N/A	In-frame deletion/insertion criterion; variant is a substitution.
PM3	N/A	Recessive disorder criterion; GNAQ-associated disease follows a dominant/somatic mosaic pattern.
PM4	N/A	Protein length change criterion; variant is a substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.