9-77794572-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002072.5(GNAQ):c.626A>G(p.Gln209Arg) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q209L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.02

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 12 ACMG points.

• PM1: In a modified_residue Deamidated glutamine; by Photorhabdus PAU_02230 (size 0) in uniprot entity GNAQ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002072.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-77794571-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1172602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-77794572-T-C is Pathogenic according to our data. Variant chr9-77794572-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 375956.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAQ	NM_002072.5	c.626A>G	p.Gln209Arg	missense_variant	5/7	ENST00000286548.9
GNAQ	XM_047423239.1	c.452A>G	p.Gln151Arg	missense_variant	5/7
GNAQ	XM_047423240.1	c.452A>G	p.Gln151Arg	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAQ	ENST00000286548.9	c.626A>G	p.Gln209Arg	missense_variant	5/7	1	NM_002072.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Sturge-Weber syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Nov 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.90		Gain of MoRF binding (P = 0.0198);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913492; hg19: chr9-80409488; COSMIC: COSV54108414; COSMIC: COSV54108414;