NM_002524.5(NRAS):c.181C>A (p.Gln61Lys) AND Large congenital melanocytic nevus

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 21, 2020
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:: RCV000114746.8

Allele description [Variation Report for NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)]

NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)

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.181C>A (p.Gln61Lys)

HGVS:

NC_000001.11:g.114713909G>T
NG_007572.1:g.7986C>A
NM_002524.5:c.181C>AMANE SELECT
NP_002515.1:p.Gln61Lys
LRG_92:g.7986C>A
NC_000001.10:g.115256530G>T
NC_000001.9:g.115058053G>T
NM_002524.4:c.181C>A
P01111:p.Gln61Lys

Protein change:

Q61K; GLN61LYS

Links:

UniProtKB: P01111#VAR_006846; OMIM: 164790.0008; dbSNP: rs121913254

NCBI 1000 Genomes Browser:

rs121913254

Molecular consequence:

NM_002524.5:c.181C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Large congenital melanocytic nevus (CMNS)
Synonyms:: Giant pigmented hairy nevus; Giant hairy nevus; Bathing trunk nevus; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0044792; MedGen: C1842036; Orphanet: 626; OMIM: 137550; Human Phenotype Ontology: HP:0005600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000148629	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2013)	somatic	literature only	PubMed (2) [See all records that cite these PMIDs] 18633438, 23392294
SCV002769261	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19966803, 22718121, 23392294, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000148629

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2013)

somatic

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002769261

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 21, 2020)

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	somatic	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis.

Dessars B, De Raeve LE, Morandini R, Lefort A, El Housni H, Ghanem GE, Van den Eynde BJ, Ma W, Roseeuw D, Vassart G, Libert F, Heimann P.

J Invest Dermatol. 2009 Jan;129(1):139-47. doi: 10.1038/jid.2008.203. Epub 2008 Jul 17.

PubMed [citation]

PMID:: 18633438

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

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000148629.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Dessars et al. (2009) identified a somatic gln61-to-lys (Q61K) mutation in the NRAS gene in 14 of 27 congenital melanocytic nevi (137550).

In affected skin samples from 8 of 13 patients with congenital melanocytic nevus syndrome (CMNS; 137550), including 4 with neurocutaneous melanosis (NCMS; 249400), Kinsler et al. (2013) identified a somatic heterozygous c.181C-A transversion in the NRAS gene, resulting in a gln61-to-lys (Q61K) substitution in the guanosine triphosphate-binding domain. The mutation was predicted to result in constitutive activation of NRAS. Neurologic samples from 5 patients from whom tissue was available were positive for a somatic Q61K mutation, and the same mutation was present in both neurologic and skin samples when available. Kinsler et al. (2013) concluded that multiple congenital melanocytic nevi and neuromelanosis, as well as associated nonmelanocytic CNS lesions, result from somatic mosaicism, and that the mutation probably occurs in a progenitor cell in the developing neural crest or neuroectoderm. The findings also suggested that the mutation may be lethal in the germline.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769261.1

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

Description

A heterozygous missense variant was identified, NM_002524.3(NRAS):c.181C>A in exon 3 of the NRAS gene. This substitution is predicted to create a minor amino acid change from a glutamine to a lysine at position 61 of the protein; NP_002515.1(NRAS):p.(Gln61Lys). The glutamine at this position has very high conservation (100 vertebrates, UCSC), and is located within the switch II region (Cirstea, I. C. et al. (2010)). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in multiple patients with congenital melanocytic naevi (ClinVar, Kinsler, V. A. et al. (2013)). In addition, functional studies show that this variant causes melanocyte survival and growth in the epidermis (Li, A. et al. (2012)). Different variants in the same codon resulting in changes to histidine, leucine, arginine, proline and glutamic acid, have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

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

Last Updated: Apr 20, 2025

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