Submissions for variant NM_002524.5(NRAS):c.35G>A (p.Gly12Asp)

gnomAD frequency: 0.00001  dbSNP: rs121913237

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158980	SCV000208919	likely pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Published functional studies suggest the variant promotes oncogenesis/leukemogenesis (Haigis et al., 2008; Wang et al., 2011; Wang et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21586752, 23687087, 26090869, 22753870, 15517309, 23303902, 31031743, 28594414, 14982869, 18372904)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813214	SCV002060959	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2019-12-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001781333	SCV002099145	pathogenic	Noonan syndrome 6	2021-03-26	criteria provided, single submitter	clinical testing	The de novo heterozygous c.35G>A (p.Gly12Asp) variant identified in the NRAS gene is a known disease-causing variant and has been reported in ClinVar a Pathogenic by multiple independent laboratories [Variation ID:39648]. Other missense variants affecting the same residue Gly12 have been reported as somatic variants in different types of cancers. The c.35G>A (p.Gly12Asp) variant identified in this individual has been reported as a somatic variant in different types of cancers [ClinVar Variation ID:39648], as well as a de novo germline variant in a patient with Noonan syndrome [for detailed clinical description see Patient# 13 in PMID: 28594414]. The variant has 0.00001314 allele frequency in the gnomAD(v3) database (2 out of 152154 heterozygous alleles, no homozygotes) suggesting it is not a common benign allele in the populations represented in that database. The variant affects a highly conserved residue and is predicted deleterious by multiple in silico tools [CADD score = 24.3, REVEL score = 0.783]. Based on the available evidence, the de novo heterozygous c.35G>A (p.Gly12Asp) variant identified inthe NRAS gene is reported as Pathogenic.
Invitae	RCV001852659	SCV002236351	pathogenic	RASopathy	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the NRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Noonan syndrome (PMID: 28594414). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39648). 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. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28098151, 28594414). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000158980	SCV002501750	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV003221788	SCV003915935	pathogenic	Autoimmune lymphoproliferative syndrome type 4		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.35G>A in Exon 2 of the NRAS gene that results in the amino acid substitution p.Gly12Asp was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variation ID: 39648]. The observed variation has been previously reported for primary melanoma of the CNS in children [Pedersen M, et.al, 2013]. Published functional studies suggests that the variant promotes oncogenesis/leukemogenesis [Wang et al., 2011]. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415756	SCV004114058	pathogenic	NRAS-related condition	2022-09-13	criteria provided, single submitter	clinical testing	The NRAS c.35G>A variant is predicted to result in the amino acid substitution p.Gly12Asp. This variant has been reported in individuals with Noonan syndrome and has been reported as a somatic variant in different types of cancers (van 't Veer et al. 1989. PubMed ID: 2674680; Matsuda et al. 2007. PubMed ID: 17332249; Mardis et al 2009. PubMed ID: 19657110; Hafner et al. 2012. PubMed ID: 22499344; MacConaill et al. 2014. PubMed ID: 25157968; Chang et al. 2015. PubMed ID: 26619011; Altmüller et al. 2017. PubMed ID: 28594414; Cifaldi et al. 2019. PubMed ID: 31031743). In ClinVar, this variant is interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/39648/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115258747-C-T). This variant is interpreted as pathogenic.
OMIM	RCV000032849	SCV000056618	pathogenic	Epidermal nevus	2013-12-05	no assertion criteria provided	literature only
OMIM	RCV000144963	SCV000191990	pathogenic	Juvenile myelomonocytic leukemia	2013-12-05	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436228	SCV000503718	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417702	SCV000503719	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427949	SCV000503720	pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439064	SCV000503721	pathogenic	Non-small cell lung carcinoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417869	SCV000503722	pathogenic	Melanoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430706	SCV000503723	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440963	SCV000503724	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424239	SCV000503725	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434517	SCV000503726	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only