Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Hospital of the University of Pennsylvania, |
RCV000203450 | SCV000258463 | pathogenic | Myelodysplastic syndrome progressed to acute myeloid leukemia | 2016-01-08 | criteria provided, single submitter | clinical testing | Activating mutation |
Gene |
RCV000380895 | SCV000330301 | pathogenic | not provided | 2017-02-01 | criteria provided, single submitter | clinical testing | The G12A missense varant in the NRAS gene has been reported previously as a somatic mutation in association with several different types of cancer and primarily affected haematopoietic and lymphoid tissues (Catalogue of Somatic Mutations in Cancer; ClinVar SCV000258463.2: Landrum et al. 2014). G12A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G12A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants in the same codon (G12S) and in a nearby residue (G13D) have been reported in the Human Gene Mutation Database in association with NRAS-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein." |
Invitae | RCV001324275 | SCV001515224 | likely pathogenic | RASopathy | 2022-11-29 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 219097). 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. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28098151, 28594414). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NRAS protein function. This variant has not been reported in the literature in individuals affected with NRAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the NRAS protein (p.Gly12Ala). |
Genome Diagnostics Laboratory, |
RCV001813426 | SCV002060960 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000434113 | SCV000503709 | pathogenic | Melanoma | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444670 | SCV000503710 | pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427550 | SCV000503711 | pathogenic | Non-small cell lung carcinoma | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433455 | SCV000503712 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444591 | SCV000503713 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426950 | SCV000503714 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437165 | SCV000503715 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418647 | SCV000503716 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425963 | SCV000503717 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only |