Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038275 | SCV000061944 | likely pathogenic | Noonan syndrome | 2014-01-08 | criteria provided, single submitter | clinical testing | The Phe156Val variant in KRAS has now been identified in three individuals in on e family with clinical features of a Noonan spectrum disorder (LMM unpublished d ata). This variant is absent from large population studies. In addition, two dif ferent amino acid changes at the same codon, Phe156Leu and Phe156Ile, have been reported to occur de novo in three individuals with a Noonan spectrum disorder ( Zenker 2007, Sovik 2007). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, this variant is likely pathogenic, though addition al studies are required to fully establish its clinical significance. |
| Gene |
RCV000157941 | SCV000207876 | pathogenic | not provided | 2018-08-14 | criteria provided, single submitter | clinical testing | The F156V variant in the KRAS gene has been reported previously in an individual with Noonan syndrome (Al Hawas, 2012). The F156V variant is not observed in large population cohorts (Lek et al., 2016). The F156V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Two pathogenic missense variants at this same residue (F156L, F156I) have been reported in association with disorders of the Noonan spectrum (Zenker et al., 2007), supporting the functional importance of this region of the protein. We interpret F156V as a pathogenic variant. |