Applied · 6

Strength Supporting Moderate Strong Very strong

✓

PS3 strong Pathogenic

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.

PMID:21083380: Q209L melan-a cell xenografts produced tumors in 6/6 sites vs 0/14 controlsPMID:29490280: conditional GNA11 Q209L mouse model recapitulated human uveal melanoma with multi-organ neoplastic lesionsOncoKB: Oncogenic classification

oncokb ↗

✓

PS4 moderate Pathogenic

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.

Absent from gnomAD v2.1v4.1and gnomAD-Canada

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP2 supporting Pathogenic

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.

GNA11 exhibits low benign missense variation in population databasesMissense gain-of-function variants at codons 183 and 209 are the established disease mechanismGNA11 is constrained for missense variation (observed vs expected missense burden consistent with constraint)

gnomad_v2 ↗gnomad_v4 ↗

✓

PP3 supporting Pathogenic

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: 0.833 (damaging)BayesDel: 0.246 (borderlinebelow 0.27 threshold)

spliceai ↗

✓

PP5 supporting Pathogenic

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 variation ID 376002: Pathogenic (1 submitter)Likely pathogenic (1 submitter)Both submissions are criteria-provided

clinvar ↗

Assessed · not applied

Pathogenic

PS1 No alternative nucleotide change at codon 209 producing the same amino acid substitution (p.Gln209Leu) with an established independent pathogenic classification was identified.

PS2 No confirmed de novo occurrence with both parents tested negative.

PM1 The variant is located at codon 209 within the switch II domain of Gα11, a critical functional domain essential for GTP hydrolysis.

PM6 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.

PP1 No cosegregation data are available.

PP4 Insufficient patient phenotype information is available for evaluation.

Benign

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS2 The variant is absent from all population databases.

BS3 Well-established in vitro and in vivo functional studies demonstrate that Q209L is a gain-of-function activating mutation, not a benign variant.

BP1 GNA11-related disorders are caused by gain-of-function missense variants at hotspot codons (primarily 209 and 183), not by truncating variants.

BP4 REVEL predicts a damaging effect (score 0.833), contradicting a benign computational assessment.

BP5 No evidence has been identified that affected individuals carrying this variant have an alternate molecular basis for their phenotype.

BP6 ClinVar reports this variant as Pathogenic and Likely Pathogenic (variation ID 376002).

N/A · 5 PVS1 · PM5 · BS4 · BP2 · BP7

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