9-77797577-C-T

Variant names:

• chr9-77797577-C-T
• rs397514698
• NM_002072.5:c.548G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002072.5(GNAQ):​c.548G>A​(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 7.86

Genes affected

GNAQ (HGNC:4390): (G protein subunit alpha q) This locus encodes a guanine nucleotide-binding protein. The encoded protein, an alpha subunit in the Gq class, couples a seven-transmembrane domain receptor to activation of phospolipase C-beta. Mutations at this locus have been associated with problems in platelet activation and aggregation. A related pseudogene exists on chromosome 2.[provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 9-77797577-C-T is Pathogenic according to our data. Variant chr9-77797577-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAQ	NM_002072.5	c.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 7	ENST00000286548.9	NP_002063.2
GNAQ	XM_047423239.1	c.374G>A	p.Arg125Gln	missense_variant	Exon 4 of 7		XP_047279195.1
GNAQ	XM_047423240.1	c.374G>A	p.Arg125Gln	missense_variant	Exon 4 of 7		XP_047279196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAQ	ENST00000286548.9	c.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 7	1	NM_002072.5	ENSP00000286548.4
GNAQ	ENST00000411677.1	c.461G>A	p.Arg154Gln	missense_variant	Exon 4 of 4	3		ENSP00000391501.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Capillary malformation Pathogenic:2

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 14, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Familial multiple nevi flammei Pathogenic:2

Oct 07, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3, PS4_MOD, PM2_SUP, PP3 -

Dec 27, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 vascular tumors, 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; Langbroek GB et al., PMID: 38013159; McNulty SN et al., PMID: 31585106; Lian CG et al., PMID: 25188413). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic somatic variant by numerous submitters, including our laboratory (ClinVar Variation ID: 50853), and it has been reported in many cases in the cancer database COSMIC (ID: COSV54106047). This variant is absent from the general population (gnomAD v4.1.0), 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 (Huang L et al., PMID: 34670408; Galeffi F, et al., PMID: 35635655; Shirley MD et al., PMID: 23656586).Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the GNAQ c.548G>A (p.Arg183Gln) variant is classified as pathogenic. -

Segmental undergrowth associated with capillary malformation Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 01, 2021

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Sturge-Weber syndrome;C0340803:Capillary malformation Pathogenic:1

Jul 19, 2016

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been described in multiple affected individuals with a mosaic etiology (PMID 26778290) -

Angioosteohypertrophic syndrome Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GNAQ-related disorder Pathogenic:1

Sep 19, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PS4, PM1, PM2, PP3 -

Sturge-Weber syndrome Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hemangiomatosis Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma Uncertain:1

Mar 28, 2023

Dave Chen Lab, Washington University School of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Somatic variant identified in a melanoma arising in a patient with Tatton-Brown Rahman Syndrome -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.95		Gain of glycosylation at T186 (P = 0.1183);.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397514698; hg19: chr9-80412493; COSMIC: COSV54106047;