Variant classification summary

NM_002067.5:c.626A>T

GNA11 · NP_002058.2:p.(Gln209Leu) · NM_002067.5

GRCh37: chr19:3118942 A>T · GRCh38: chr19:3118944 A>T

Gene: GNA11 Transcript: NM_002067.5

Final call

Pathogenic

PS3 strong PS4 moderate PM2 supporting PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

GNA11

Transcript

NM_002067.5

Protein

NP_002058.2:p.(Gln209Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

GNA11 c.626A>T (p.Gln209Leu) is a well-characterized gain-of-function missense variant at codon 209 within the switch II functional domain, a critical region for GTPase activity and a mutational hotspot in GNA11/GNAQ-driven melanocytic neoplasms.

2

Functional studies demonstrate a deleterious effect: Q209L-transduced melan-a cells produced rapidly growing tumors in all 6 injection sites in immunocompromised mice compared to 0 of 14 controls (PMID:21083380), and a conditional GNA11 Q209L knock-in mouse model recapitulated human Gq-associated melanomas with multi-organ neoplastic lesions (PMID:29490280).

3

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, yet is recurrently observed in affected tissue: COSMIC reports 442 somatic occurrences, and it has been identified as the predominant codon 209 mutation in uveal melanoma, blue nevi, cutaneous melanoma, and phakomatosis pigmentovascularis.

4

Two clinical laboratories in ClinVar classify this variant as Pathogenic or Likely Pathogenic (variation ID 376002). In silico prediction with REVEL (score 0.833) supports a damaging effect. GNA11 exhibits low benign missense variation in population databases, consistent with PP2.

5

Applying generic ACMG/AMP 2015 combination rules: PS3 (strong), PM1 (moderate), PS4 (moderate), PM2 (supporting), PP2 (supporting), PP3 (supporting), PP5 (supporting) support a classification of 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	This variant is a missense change (c.626A>T, p.Gln209Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). Generic PVS1 framework does not apply.
PS1	Not assessed	No alternative nucleotide change at codon 209 producing the same amino acid substitution (p.Gln209Leu) with an established independent pathogenic classification was identified.
PS2	Not met	No confirmed de novo occurrence with both parents tested negative. A mosaic case was reported in phakomatosis pigmentovascularis (PMID:26778290) but parental DNA was not tested and the event was postzygotic mosaic, not germline.
PS3	Met	Well-established in vitro and in vivo functional studies demonstrate that GNA11 Q209L is a gain-of-function activating mutation. Van Raamsdonk et al. (2010) showed Q209L-transduced melan-a cells produced rapidly growing tumors in 6/6 injection sites in immunocompromised mice versus 0/14 controls. Moore et al. (2018) generated a conditional GNA11 Q209L mouse model that recapitulated human Gq-associated melanomas with pigmented neoplastic lesions in skin, eye, and leptomeninges. These independent lines of functional evidence confirm a deleterious gain-of-function effect.	oncokb
PS4	Met	This variant is highly enriched in affected individuals compared to the general population. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, yet is recurrently observed in affected tissue: COSMIC reports 442 somatic occurrences predominantly in uveal melanoma and blue nevi; it has been reported in multiple publications as the predominant GNA11 codon 209 mutation in melanocytic neoplasms; and is classified as Pathogenic/Likely Pathogenic in ClinVar. The extreme disparity between population absence and disease-associated presence supports a pathogenic role, though evidence derives predominantly from somatic and mosaic contexts.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PS5	Not met	No different missense change at the same residue (Gln209) has been independently established as pathogenic in a germline context. While Q209P, Q209L (by alternative nucleotide), and other codon 209 changes are observed somatically, they lack independent germline pathogenicity classification meeting PS5 requirements.
PM1	Not assessed	The variant is located at codon 209 within the switch II domain of Gα11, a critical functional domain essential for GTP hydrolysis. Codon 209 is a well-established mutational hotspot in GNA11 and GNAQ, with multiple independent pathogenic missense substitutions reported at this residue (Q209L, Q209P, Q209H). Mutations at this hotspot result in constitutive activation of downstream MAPK signaling.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, indicating it is extremely rare or absent in the general population, consistent with a pathogenic role.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No different pathogenic missense change at the same residue (Gln209) with a confirmed germline pathogenic classification was identified for PM5 comparator analysis. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics.
PM6	Not met	The variant was reported in a mosaic state in a patient with phakomatosis pigmentovascularis (PMID:26778290), but parents were not tested and the event was postzygotic mosaic rather than germline de novo. PM6 requires a confirmed de novo occurrence with both parents tested negative, which is not met.
PP1	Not met	No cosegregation data are available. All reported cases with this variant are sporadic, typically due to postzygotic mosaicism. Familial transmission has not been described, likely because the variant is lethal when constitutional and non-mosaic.
PP2	Met	GNA11 has a low rate of benign missense variation in population databases, and missense variants are the predominant pathogenic mechanism (gain-of-function at hotspot codons 183 and 209). The gene is constrained for missense variation, supporting PP2.	gnomad_v2 gnomad_v4
PP3	Met	In silico prediction supports a deleterious effect: REVEL score is 0.833 (strongly damaging). SpliceAI predicts no splicing impact (max delta score 0.01). BayesDel score is 0.246, borderline below typical damaging threshold. The REVEL score, combined with the location in a critical functional domain, supports a deleterious computational prediction.	revel bayesdel spliceai
PP4	Not assessed	Insufficient patient phenotype information is available for evaluation. ClinVar submissions list conditions as 'not provided' and 'see cases' without detailed clinical descriptions. The phenotypes associated with this variant (uveal melanoma, phakomatosis pigmentovascularis, cutaneous melanoma, blue nevi) are consistent with GNA11-related disorders, but specific patient-level phenotype data are not available for formal PP4 assessment.	clinvar
PP5	Met	Two clinical laboratories have submitted this variant to ClinVar (variation ID 376002) with classifications of Pathogenic (SCV002525654, Seattle Children's Hospital) and Likely Pathogenic (SCV003804872, University Hospital Muenster). Both submissions are criteria-provided, single-submitter classifications. While no expert panel review is available, multiple independent clinical laboratories have reached concordant pathogenic conclusions.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 allele frequency threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 allele frequency threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant is absent from all population databases. No evidence of observation in healthy homozygous adults or at allele frequencies consistent with recessive inheritance.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Well-established in vitro and in vivo functional studies demonstrate that Q209L is a gain-of-function activating mutation, not a benign variant. Van Raamsdonk et al. (2010) showed Q209L produced tumors in 6/6 xenograft sites. Moore et al. (2018) demonstrated GNA11 Q209L mice recapitulate human melanoma. No functional evidence supports a benign effect.
BS4	N/A	BS4 requires demonstration of non-segregation in affected family members. This variant occurs predominantly in somatic/mosaic contexts with no multigenerational families available for segregation analysis. BS4 cannot be meaningfully assessed.
BP1	Not met	GNA11-related disorders are caused by gain-of-function missense variants at hotspot codons (primarily 209 and 183), not by truncating variants. BP1, which applies when truncating variants are the primary disease mechanism, is not applicable to GNA11.
BP2	N/A	GNA11-related conditions are dominant (typically mosaic-dominant). This variant has never been reported in biallelic form. BP2, which applies to recessive disorders, is not applicable.
BP4	Not met	REVEL predicts a damaging effect (score 0.833), contradicting a benign computational assessment. SpliceAI predicts no splicing impact (max delta 0.01), but this single benign line is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact.	revel spliceai
BP5	Not met	No evidence has been identified that affected individuals carrying this variant have an alternate molecular basis for their phenotype. BP5 requires demonstration of a definitive alternate genetic cause in a case harboring this variant.
BP6	Not met	ClinVar reports this variant as Pathogenic and Likely Pathogenic (variation ID 376002). No reputable source classifies this variant as benign or likely benign. BP6 requires a reputable source to report the variant as benign.	clinvar
BP7	N/A	This variant is a missense change (c.626A>T, p.Gln209Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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