Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000220187 | SCV001335321 | pathogenic | RASopathy | 2020-03-16 | reviewed by expert panel | curation | The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2. |
| Laboratory for Molecular Medicine, |
RCV000844674 | SCV000271240 | likely pathogenic | Noonan syndrome | 2015-07-28 | criteria provided, single submitter | clinical testing | The p.Asn122Asp variant in MAP2K1 has been identified by our laboratory as a de novo occurrence in 1 individual with clinical features of Noonan syndrome. It wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Asn122Asp variant is likely pathogenic. |
| Fulgent Genetics, |
RCV000763361 | SCV000894052 | likely pathogenic | Noonan syndrome 1; Cardiofaciocutaneous syndrome 3 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000220187 | SCV000947966 | likely pathogenic | RASopathy | 2021-08-27 | criteria provided, single submitter | clinical testing | |
| MNM Diagnostics | RCV001312196 | SCV001502658 | pathogenic | Cardiofaciocutaneous syndrome 3 | 2020-02-10 | criteria provided, single submitter | clinical testing | According to ACMG Guidelines, the variant meets the following criteria of pathogenicity: PS2, PS4, PM2, PP2, PP3, PP4. This is a de novo variant of a missense heterozygotic mutation in exon 3 of MAP2K1 gene in position c.364A>G. The change results in the asparagine to aspartate substitution in codon 122. MAP2K1 mutations are responsible for the Cardio-facio-cutaneous Syndrome type 3 (CFCS) observed as well in the proband. |