Submissions for variant NM_002072.5(GNAQ):c.548G>A (p.Arg183Gln)

dbSNP: rs397514698

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000533476	SCV000622156	pathogenic	Capillary malformation; Sturge-Weber syndrome	2016-07-19	criteria provided, single submitter	clinical testing	This variant has been described in multiple affected individuals with a mosaic etiology (PMID 26778290)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526543	SCV001736968	pathogenic	Hemangiomatosis		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526638	SCV001737069	pathogenic	Angioosteohypertrophic syndrome		criteria provided, single submitter	clinical testing
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz	RCV001705695	SCV001934206	pathogenic	Segmental undergrowth associated with capillary malformation	2021-04-06	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254275	SCV002525658	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing	This variant is a recurrent pathogenic variant that accounts for ~90% of individuals with non-syndromic port-wine stains and Sturge-Weber syndrome (MIM: 185300), which, along with congenital capillary malformations (MIM: 163000), is included within GNAQ-related disorder (PMID: 25374402, PMID: 23656586).
Institute of Human Genetics, University of Leipzig Medical Center	RCV002294003	SCV002587081	likely pathogenic	Familial multiple nevi flammei	2022-10-07	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4_MOD, PM2_SUP, PP3
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000043593	SCV004176929	pathogenic	Capillary malformation	2023-10-14	criteria provided, single submitter	clinical testing	A GNAQ c.548G>A (p.Arg183Gln) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with Sturge-Weber syndrome, nonsyndromic port-wine stains, and phakomatosis pigmentovascularis with capillary malformation and hemihypertrophy (Shirley MD et al., PMID: 23656586; Nakashima M et al., PMID: 25374402; Frigerio A et al., PMID: 26192947; Thomas AC et al., PMID: 26778290; He R et al., PMID: 32613723). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters (ClinVar ID: 50853), and it has been reported in multiple cases in the cancer database COSMIC (Genomic ID: COSV54106047). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the GTP-binding site of the G2 motif, which is defined as a critical functional domain (Nakashima M et al., PMID: 25374402). Computational predictors indicate that the GNAQ c.548G>A (p.Arg183Gln) variant is damaging, evidence that correlates with impact on GNAQ function. In support of this prediction, functional studies show that this variant increases activation of the mitogen-activated protein kinase (MAPK) pathway and increases angiopoietin-2 expression (Shirley MD et al., PMID: 23656586; Huang L et al., PMID: 34670408). GNAQ is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAQ c.548G>A (p.Arg183Gln) variant is classified as pathogenic.
OMIM	RCV000043592	SCV000071610	pathogenic	Sturge-Weber syndrome	2014-12-01	no assertion criteria provided	literature only
OMIM	RCV000043593	SCV000071611	pathogenic	Capillary malformation	2014-12-01	no assertion criteria provided	literature only
Dave Chen Lab, Washington University School of Medicine	RCV003221795	SCV003914813	uncertain significance	Melanoma	2023-03-28	no assertion criteria provided	research	Somatic variant identified in a melanoma arising in a patient with Tatton-Brown Rahman Syndrome