ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.179G>A (p.Gly60Glu) (rs267606920)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158982 SCV000208921 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The G60E variant in the NRAS gene has been reported previously as both sporadic and inherited in multiple individuals with Noonan syndrome (Cirstea et al., 2010; Altmuller et al., 2017). The G60E variant is observed in 1/30952 (0.003%) alleles in large population cohorts (Lek et al., 2016). The G60E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate that the G60E variant causes enhanced MAPK phosphorylation (Runtuwene et al., 2011; Cirstea et al., 2010). Additionally, the neighboring codon (G61) is a known hotspot for pathogenic variants. We interpret G60E as a pathogenic variant.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago 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 ( 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
OMIM RCV000014917 SCV000035173 pathogenic Noonan syndrome 6 2010-01-01 no assertion criteria provided literature only
GeneReviews RCV000208552 SCV000264348 pathogenic Noonan syndrome 1 2016-02-25 no assertion criteria provided literature only

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