ClinVar Genomic variation as it relates to human health
NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)
Variation ID: 13903 Accession: VCV000013903.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.2 1: 114713911 (GRCh38) [ NCBI UCSC ] 1: 115256532 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 1, 2016 Feb 14, 2024 Mar 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002524.5:c.179G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002515.1:p.Gly60Glu missense NC_000001.11:g.114713911C>T NC_000001.10:g.115256532C>T NG_007572.1:g.7984G>A LRG_92:g.7984G>A LRG_92t1:c.179G>A LRG_92p1:p.Gly60Glu P01111:p.Gly60Glu - Protein change
- G60E
- Other names
- p.G60E:GGA>GAA
- Canonical SPDI
- NC_000001.11:114713910:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NRAS | - | - |
GRCh38 GRCh37 |
283 | 305 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2022 | RCV000158982.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 1, 2017 | RCV000014917.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 11, 2022 | RCV001382056.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2023 | RCV003415702.4 | |
not provided (1) |
no classification provided
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- | RCV000208552.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 6
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000678203.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Feb 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000208921.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jun 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927736.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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NRAS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116484.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001580663.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Jan 01, 2010)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035173.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2017 |
Comment on evidence:
In 3 patients from 2 unrelated families with Noonan syndrome-6 (NS6; 613224), Cirstea et al. (2010) identified a heterozygous 179G-A transition in exon 3 of … (more)
In 3 patients from 2 unrelated families with Noonan syndrome-6 (NS6; 613224), Cirstea et al. (2010) identified a heterozygous 179G-A transition in exon 3 of the NRAS gene, resulting in a gly60-to-glu (G60E) substitution in a conserved residue in the switch 2 region. One proband had a de novo mutation, whereas the other inherited it from his affected mother. In vitro functional expression studies showed that the mutant protein resulted in enhanced downstream phosphorylation in the presence of serum, and that the G60E mutant NRAS protein accumulated constitutively in the active GTP-bound form, although it appeared to be resistant to GAP stimulation. By targeted next-generation sequencing in a father and daughter with Noonan syndrome, Ekvall et al. (2015) identified heterozygosity for the G60E mutation in the NRAS gene. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Noonan syndrome 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000264348.2
First in ClinVar: Mar 01, 2016 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Noonan Syndrome. | Adam MP | - | 2022 | PMID: 20301303 |
Genotype and phenotype spectrum of NRAS germline variants. | Altmüller F | European journal of human genetics : EJHG | 2017 | PMID: 28594414 |
Mutation in NRAS in familial Noonan syndrome--case report and review of the literature. | Ekvall S | BMC medical genetics | 2015 | PMID: 26467218 |
A restricted spectrum of NRAS mutations causes Noonan syndrome. | Cirstea IC | Nature genetics | 2010 | PMID: 19966803 |
Text-mined citations for rs267606920 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.