Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clinical Genomics Laboratory, |
RCV004563306 | SCV005049541 | pathogenic | Sturge-Weber syndrome | 2023-12-18 | criteria provided, single submitter | clinical testing | A GNAQ c.626A>T (p.Gln209Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with various forms of nevi (Bender RP et al., PMID: 23599145; Colebatch AJ et al., PMID: 35439782; Van Raamsdonk CD et al., PMID: 19078957) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV54105914). This variant is absent from the general population database (gnomAD v4.0.0), indicating it is not a common variant. This variant resides within the GTP-binding site of the ras-like domain, amino acids 40-353, 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>T (p.Gln209Leu) 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 leading to cellular transformation (Galeffi F et al., PMID: 35635655; Thomas AC et al., PMID: 26778290; Van Raamsdonk CD et al., PMID: 19078957). Other variants in the same codon, p.Gln209His, p.Gln209Arg and p.Gln209Pro, have been reported in multiple individuals and are considered pathogenic (Van Raamsdonk CD et al., PMID: 19078957; ClinVar IDs: 1172602, 1172601, 375956, 375957). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAQ c.626A>T (p.Gln209Leu) variant is classified as pathogenic. |