NM_002524.5(NRAS):c.179G>A (p.Gly60Glu) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 11, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001382056.6

Allele description [Variation Report for NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)]

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

Gene:

NRAS:NRAS proto-oncogene, GTPase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.2

Genomic location:

Preferred name:

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

Other names:

p.G60E:GGA>GAA

HGVS:

NC_000001.11:g.114713911C>T
NG_007572.1:g.7984G>A
NM_002524.5:c.179G>AMANE SELECT
NP_002515.1:p.Gly60Glu
LRG_92t1:c.179G>A
LRG_92:g.7984G>A
LRG_92p1:p.Gly60Glu
NC_000001.10:g.115256532C>T
NM_002524.3:c.179G>A
NM_002524.4:c.179G>A
P01111:p.Gly60Glu

Protein change:

G60E; GLY60GLU

Links:

UniProtKB: P01111#VAR_063086; OMIM: 164790.0005; dbSNP: rs267606920

NCBI 1000 Genomes Browser:

rs267606920

Molecular consequence:

NM_002524.5:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580663	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 11, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19966803, 26467218, 28594414, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580663

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 11, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A restricted spectrum of NRAS mutations causes Noonan syndrome.

Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, König R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, et al.

Nat Genet. 2010 Jan;42(1):27-9. doi: 10.1038/ng.497. Epub 2009 Dec 6.

PubMed [citation]

PMID:: 19966803
PMCID:: PMC3118669

Mutation in NRAS in familial Noonan syndrome--case report and review of the literature.

Ekvall S, Wilbe M, Dahlgren J, Legius E, van Haeringen A, Westphal O, Annerén G, Bondeson ML.

BMC Med Genet. 2015 Oct 14;16:95. doi: 10.1186/s12881-015-0239-1. Review.

PubMed [citation]

PMID:: 26467218
PMCID:: PMC4607013

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001580663.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 10, 2024

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