1-114713911-C-T

Variant names:

• chr1-114713911-C-T
• rs267606920
• NM_002524.5:c.179G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PP1 PS3_Moderate PS4 PS2

This summary comes from the ClinGen Evidence Repository: The NM_002524.5:c.179G>A variant in NRAS is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 60 (p.Gly60Glu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006482 (1/15428 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 13 probands with RASopathy (PS4; PMIDs: 19966803, 26467218, 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). This variant has been identified as a de novo occurrence with confirmed parental relationships in 4 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 19966803 and 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). The variant has been reported to segregate with RASopathy in 5 affected family members from 3 family(ies (PP1; PMIDs: 19966803, 26467218, 28594414). MEK and ERK activation in COS-7 cells showed increased phophorylation indicating that this variant impacts protein function (PMID:19966803)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA257021/MONDO:0021060/039

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 7.80
• Publications: 65 publications found

Genes affected

NRAS (HGNC:7989): (NRAS proto-oncogene, GTPase) This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. [provided by RefSeq, Jun 2011]

NRAS Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Costello syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRAS	NM_002524.5	c.179G>A	p.Gly60Glu	missense_variant	Exon 3 of 7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5	c.179G>A	p.Gly60Glu	missense_variant	Exon 3 of 7	1	NM_002524.5	ENSP00000358548.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459638 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110040

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000517 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

NRAS-related disorder Pathogenic:2

Mar 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 22, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Noonan syndrome 6 Pathogenic:2

Aug 01, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Feb 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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)

Jun 11, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Pathogenic:2

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_002524.5:c.179G>A variant in NRAS is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 60 (p.Gly60Glu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006482 (1/15428 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 13 probands with RASopathy (PS4; PMIDs: 19966803, 26467218, 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). This variant has been identified as a de novo occurrence with confirmed parental relationships in 4 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 19966803 and 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). The variant has been reported to segregate with RASopathy in 5 affected family members from 3 family(ies (PP1; PMIDs: 19966803, 26467218, 28594414). MEK and ERK activation in COS-7 cells showed increased phophorylation indicating that this variant impacts protein function (PMID: 19966803)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024)

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Cardiovascular phenotype Pathogenic:1

Oct 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Noonan syndrome 1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.95
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.95
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606920; hg19: chr1-115256532; COSMIC: COSV54736394; COSMIC: COSV54736394;