ClinVar

Description

A GNAQ c.626A>G (p.Gln209Arg) variant was identified at an allelic fraction consistent with somatic origin. The GNAQ c.626A>G (p.Gln209Arg) variant has been described in numerous patients affected with Sturge-Weber syndrome, choroidal hemangioma, non-syndromic capillary malformations, and cherry angiomas (Francis JH et al., PMID: 30537484; Le Guin CHD et al., PMID: 31336681; Galeffi F et al., PMID: 35635655; Klebanov N et al., PMID: 30601876). This variant has been reported in eleven cases in the cancer database COSMIC (Genomic Mutation ID: COSV54108414) and is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. It lies within the GTP-binding site of the ras-like domain of GNAQ, which is defined as a critical functional domain (Markby DW et al., PMID: 8266082; Van Raamsdonk CD et al., PMID: 19078957). Computational predictors indicate that the GNAQ c.626A>G (p.Gln209Arg) variant is damaging, evidence that correlates with impact on GNAQ function. In support of this prediction, functional studies show increased activation of mitogen-activated protein kinase (MAPK) signaling pathways and associated downstream transcriptional programs in microvascular endothelial cells (Galeffi F et al., PMID: 35635655). The GNAQ gene is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Other variants in the same codon, p.Gln209His, p.Gln209Leu and p.Gln209Pro, have been reported in multiple individuals and are considered pathogenic (Van Raamsdonk CD et al., PMID: 19078957; ClinVar IDs: 1172602, 1172601, 375955, 375957). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAQ c.626A>G (p.Gln209Arg) variant is classified as pathogenic.