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

dbSNP: rs121913254

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696329	SCV000824885	uncertain significance	RASopathy	2018-01-29	criteria provided, single submitter	curation	This sequence change replaces glutamine with lysine at codon 61 of the NRAS protein (p.Gln61Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). While this variant has been published in the literature (PMID: 23392294), it has not been reported in the germline of an individual with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 73058). This variant has been reported as a recurrent variant in melanoma tumors (PMID: 23392294), colorectal tumors (PMID: 27050078, 23400451), thyroid tumors (PMID: 28780248), squamous cell lung tumors (PMID: 25348872), neuroblastoma tumors (PMID: 26821351), and gynecological tumors (PMID: 24671188). Experimental studies have shown that this missense change p.Gln61Lys, results in cytoskeletal changes in melanocyte cell lines, reduces apoptosis, and results in hyperpigmented skin in transgenic mice who develop cutaneous metastasizing melanoma (PMID: 22718121, 18668139, 15899789). However, in a thyroid epithelial cell line, this variant alone resulted in zero tumor instances (PMID: 10821536). In zebrafish, expression of human NRAS p.Q61K in melanocytes results in the growth of pigmented lesions that rarely progress to melanoma. (PMID: 24148783). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001092890	SCV001249621	pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000114746	SCV002769261	pathogenic	Large congenital melanocytic nevus	2020-05-21	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000114746	SCV000148629	pathogenic	Large congenital melanocytic nevus	2013-09-01	no assertion criteria provided	literature only
OMIM	RCV000144964	SCV000191991	pathogenic	Neurocutaneous melanocytosis	2013-09-01	no assertion criteria provided	literature only
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust	RCV000626456	SCV000734846	drug response	Ras Inhibitor response	2017-11-27	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000662267	SCV000784595	likely pathogenic	Vascular Tumors Including Pyogenic Granuloma	2015-02-19	no assertion criteria provided	literature only