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

gnomAD frequency: 0.00001  dbSNP: rs267606920

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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, 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 (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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382056	SCV001580663	pathogenic	RASopathy	2024-07-16	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs267606920, gnomAD 0.007%). 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. ClinVar contains an entry for this variant (Variation ID: 13903). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NRAS function (PMID: 19966803). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415702	SCV004116484	pathogenic	NRAS-related disorder	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.
Ambry Genetics	RCV004984642	SCV005466379	pathogenic	Cardiovascular phenotype	2024-10-29	criteria provided, single submitter	clinical testing	The p.G60E pathogenic mutation (also known as c.179G>A), located in coding exon 2 of the NRAS gene, results from a G to A substitution at nucleotide position 179. The glycine at codon 60 is replaced by glutamic acid, an amino acid with similar properties. This variant has been reported in subjects with features of Noonan syndrome and has been reported as a de novo variant (Cirstea IC et al. Nat Genet, 2010 Jan;42:27-9; Runtuwene V et al. Dis Model Mech, 2011 May;4:393-9; Kraoua L et al. Am J Med Genet A, 2012 Oct;158A:2407-11; Ekvall S et al. BMC Med Genet, 2015 Oct;16:95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003415702	SCV005900565	pathogenic	NRAS-related disorder	2024-03-22	criteria provided, single submitter	clinical testing	Missense variation is an established mechanism of disease for NRAS-related disorders (PMID: 28594414). The c.179G>A (p.Gly60Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a recurrent, known Pathogenic variant that has been previously reported as a heterozygous change in the de novo state (PMID: 19966803, 22887781) and co-segregating with disease in familial cases of Noonan syndrome (PMID: 19966803, 26467218, 28594414, 22887781). The c.179G>A (p.Gly60Glu) variant is located in a mutational hotspot for pathogenic variations associated with Noonan syndrome (PMID: 28594414). In vitro functional studies demonstrated that the c.179G>A (p.Gly60Glu) variant results in upregulation of MAPK (PMID: 19966803), while in vivo studies in zebrafish embryos revealed severe developmental defects that resemble those observed in Noonan syndrome (PMID: 21263000). The c.179G>A (p.Gly60Glu) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0003% (2/779002) and absent in the homozygous state. However, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD v4 database. Based on the available evidence, c.179G>A (p.Gly60Glu) is classified as Pathogenic.
OMIM	RCV000014917	SCV000035173	pathogenic	Noonan syndrome 6	2010-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000208552	SCV000264348	not provided	Noonan syndrome 1		no assertion provided	literature only