Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000158982 | SCV000208921 | pathogenic | not provided | 2022-02-23 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate variant results in enhanced phosphorylation of MEK and ERK and upregulation of MAPK (Runtuwene V et al., 2011; Cirstea IC et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19966803, 22887781, 26467218, 24803665, 32369273, 28594414, 21263000) |
Center for Genomics, |
RCV000014917 | SCV000678203 | pathogenic | Noonan syndrome 6 | 2017-08-01 | criteria provided, single submitter | clinical testing | NRAS NM_002524 exon3 p.Gly60Glu (c.179G>A): This variant has been reported in the literature in 3 individuals with Noonan syndrome, segregating with disease in 1 affected family member. Of note, at least one of these individuals was also reported to have this variant de novo (Cirstea 2010 PMID:19966803). This variant has also been identified by our laboratory as de novo in 1 individual with clinical suspicion of a RASopathy. This variant is present in 1/15004 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs267606920). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variant ID: 13903). Furthermore, in vitro functional studies predict that this variant will impact the protein (Cirstea 2010 PMID:19966803). In summary, this variant is classified as pathogenic based on the data above (segregation studies, presence as a de novo, absence from controls, functional studies). |
Blueprint Genetics | RCV000158982 | SCV000927736 | pathogenic | not provided | 2018-06-11 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001382056 | SCV001580663 | pathogenic | RASopathy | 2022-07-11 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NRAS function (PMID: 19966803). 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. ClinVar contains an entry for this variant (Variation ID: 13903). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19966803, 26467218, 28594414). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606920, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 60 of the NRAS protein (p.Gly60Glu). |
Prevention |
RCV003415702 | SCV004116484 | pathogenic | NRAS-related condition | 2023-03-03 | criteria provided, single submitter | clinical testing | The NRAS c.179G>A variant is predicted to result in the amino acid substitution p.Gly60Glu. This variant has been reported to be causative for Noonan syndrome in both familial and sporadic cases and was shown to have occurred de novo in the sporadic cases (Cirstea et al. 2010. PubMed ID: 19966803; Ekvall et al. 2015. PubMed ID: 26467218; Altmüller et al. 2017. PubMed ID: 28594414). At PreventionGenetics, we previously identified this variant in other patients with a diagnosis of Noonan-spectrum disorders. This variant has also been reported to impact NRAS protein function (Cirstea et al. 2010. PubMed ID: 19966803). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115256532-C-T). This variant is interpreted as pathogenic. |
OMIM | RCV000014917 | SCV000035173 | pathogenic | Noonan syndrome 6 | 2010-01-01 | no assertion criteria provided | literature only | |
Gene |
RCV000208552 | SCV000264348 | not provided | Noonan syndrome 1 | no assertion provided | literature only |