Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000037590 | SCV000061248 | likely pathogenic | Cardio-facio-cutaneous syndrome | 2014-10-21 | criteria provided, single submitter | clinical testing | The p.Leu42Phe variant in MAP2K1 has been previously identified in two individua ls with clinical features of Cardio-facio-cutaneous syndrome (Dentici 2009, LMM unpublished data) and was identified to occur de novo in one individual (Dentici 2009). It was absent from large population studies. Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein. In summary, the p.Leu42Phe variant is likely pathogenic, th ough additional studies are required to fully establish its clinical significanc e. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001582510 | SCV001821403 | uncertain significance | not specified | 2021-08-27 | criteria provided, single submitter | clinical testing | Variant summary: MAP2K1 c.124C>T (p.Leu42Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD). c.124C>T has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Dentici_2009, Alfieri_2012, Bessis_2019, Leoni_2020). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Jindal_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Labcorp Genetics |
RCV003539771 | SCV004297620 | likely pathogenic | RASopathy | 2023-04-14 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MAP2K1 function (PMID: 28049852, 29753091). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 44587). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome and/or clinical features of MAP2K1-related conditions (PMID: 19156172, 29907801, 30141192; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 42 of the MAP2K1 protein (p.Leu42Phe). |
| Pediatric Genetics Clinic, |
RCV001787832 | SCV001712197 | pathogenic | Cardiofaciocutaneous syndrome 3 | 2021-05-13 | no assertion criteria provided | clinical testing |