Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV002254481 | SCV002525684 | pathogenic | Parkes Weber syndrome | criteria provided, single submitter | clinical testing | This deletion of 15 nucleotides results in an in-frame deletion adjacent to the proteins negative regulatory domain. It has been proposed, but not experimentally demonstrated, that this variant increases MEK1 activity (PMID: 28190454). This variant has previously been reported in at least three unrelated individuals with arteriovenous malformations (AVMs) or an intramuscular fast-flow vascular anomaly (IFVA) (PMID: 28190454, 31486960). The origin of the mutation was somatic in each individual. Somatic activating mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1) are a known cause of AVMs. | |
| Clinical Genomics Laboratory, |
RCV003458851 | SCV004176898 | likely pathogenic | Vascular malformation | 2023-08-26 | criteria provided, single submitter | clinical testing | The MAP2K1 c.173_187del (p.Gln58_Glu62del) variant was identified at an allelic fraction consistent with somatic origin. The MAP2K1 c.173_187del (p.Gln58_Glu62del) variant has been reported in three individuals with arteriovenous malformations (Couto JA et al., PMID: 28190454; Goss JA et al., PMID: 31486960). This variant has been reported in three cases in the cancer database COSMIC (Genomic Mutation ID: COSV61072149), and it has been reported in the ClinVar database as pathogenic by one submitter (ClinVar Variation ID: 1691383). The MAP2K1 c.173_187del (p.Gln58_Glu62del) variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant resides within an N-terminus region, amino acids 43-61, of MAP2K1 that is defined as a critical functional domain (Xu Be et al., PMID: 10567369; Gelb BD et al., PMID: 29493581). This variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 5 amino acids in a non-repeat region. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the MAP2K1 c.173_187del (p.Gln58_Glu62del) variant is classified as likely pathogenic. |