Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000150884 | SCV000198458 | pathogenic | Noonan syndrome; Cardio-facio-cutaneous syndrome | 2018-02-15 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Gene |
RCV000493013 | SCV000582867 | pathogenic | not provided | 2018-04-30 | criteria provided, single submitter | clinical testing | The F156I missense variant in the KRAS gene has been reported de novo in an individual with Noonan/CFC syndrome (Zenker et al., 2007). The F156I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F156I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (F156L, V152G, D153V) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. |
| DASA | RCV001813760 | SCV002061164 | pathogenic | Noonan syndrome 3 | 2022-01-05 | criteria provided, single submitter | clinical testing | The c.466T>A;p.(Phe156Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 163758; PMID: 17056636; 21779504; 17211612) - PS4_supporting The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 17056636) - PS2.This variant is not present in population databases (rs397517042, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 45127; PMID: 17601930; 17056636) - PM5. Missense variant in KRAS that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. |