Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001250384 | SCV001424736 | pathogenic | RASopathy | 2020-06-25 | reviewed by expert panel | curation | The c.323G>T (p.Arg108Leu) variant in MAP2K1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in 2 probands, one of whom had maternity and paternity confirmed (PS2, PM6; Fulgent Genetics and Baylor Genetics internal data, ClinVar SCV000894927.1). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg108Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PM2, PM6, PP2, PP3. |
| Gene |
RCV000388257 | SCV000330361 | uncertain significance | not provided | 2016-03-23 | criteria provided, single submitter | clinical testing | The R108L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R108L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the protein kinase domain that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Fulgent Genetics, |
RCV000763976 | SCV000894927 | uncertain significance | Noonan syndrome 1; Cardiofaciocutaneous syndrome 3 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Equipe Genetique des Anomalies du Developpement, |
RCV001027695 | SCV001190269 | likely pathogenic | Cardiofaciocutaneous syndrome 3 | 2019-06-28 | criteria provided, single submitter | clinical testing |