Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000155926 | SCV000205637 | pathogenic | Noonan syndrome | 2015-11-12 | criteria provided, single submitter | clinical testing | The p.Met72Leu variant in KRAS (c.214A>T) has been identified by our laboratory in 1 individual with clinical features of Noonan syndrome and segregated with di sease in 1 affected relative. Additionally, a different nucleotide change (c.214 A>C ) resulting in the same p.Met72Leu variant has also been reported in 1 indiv idual with clinical features of Noonan syndrome, who was de novo for the variant , and passed the variant on to 2 relatives with clinical features of Noonan sy ndrome (Brasil 2012). Both variants were absent from large population studies. I n summary, this variant meets our criteria to be classified as pathogenic for No onan syndrome in an autosomal dominant manner based upon de novo occurrence, seg regation studies, and absence from controls. |
| Invitae | RCV001857536 | SCV002266330 | likely pathogenic | RASopathy | 2020-12-19 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different variant (c.214A>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 22488932). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 179141). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 72 of the KRAS protein (p.Met72Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001857536 | SCV003844819 | pathogenic | RASopathy | 2023-02-15 | criteria provided, single submitter | clinical testing | Variant summary: KRAS c.214A>T (p.Met72Leu) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251324 control chromosomes (gnomAD). Another variant (c.214A>C) causing the same amino acid change (i.e. p.Met72Leu) has been reported in the literature, segregating with disease, in 3 affected individuals from one family affected with Noonan syndrome (Brasil_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for c.214A>T to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. One of the submitters cites evidence of the variant identified in 1 individual with clinical features of Noonan syndrome and segregated with disease in 1 affected relative (SCV000205637.4). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Based on the evidence outlined above, the variant was classified as pathogenic. |