Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000158980 | SCV000208919 | pathogenic | not provided | 2025-01-08 | criteria provided, single submitter | clinical testing | Reported previously as a somatic variant in association with several different types of cancer; most commonly in hematopoietic and lymphoid neoplasms (PMID: 15517309, 14982869, 22753870, 26090869); Published functional studies suggest the variant promotes oncogenesis/leukemogenesis and in a mouse model, heterozygosity caused embryonic lethality compared to controls (PMID: 33681212, 18372904, 21586752, 23687087); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 21586752, 23687087, 26090869, 22753870, 15517309, 23303902, 31031743, 33681212, 14982869, 28594414, 18372904, 35753512) |
Genome Diagnostics Laboratory, |
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. |
Labcorp Genetics |
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. |
Ai |
RCV000158980 | SCV002501750 | pathogenic | not provided | 2021-07-22 | criteria provided, single submitter | clinical testing | |
Lifecell International Pvt. |
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. | |
Prevention |
RCV003415756 | SCV004114058 | pathogenic | NRAS-related disorder | 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. |
Ambry Genetics | RCV004018703 | SCV005019311 | pathogenic | Cardiovascular phenotype | 2024-01-12 | criteria provided, single submitter | clinical testing | The p.G12D pathogenic mutation (also known as c.35G>A), located in coding exon 1 of the NRAS gene, results from a G to A substitution at nucleotide position 35. The glycine at codon 12 is replaced by aspartic acid, an amino acid with similar properties. This mutation has been detected in various types of cancers (van 't Veer LJ et al. Mol Cell Biol, 1989 Jul;9:3114-6; Vogelstein B et al. Genes Chromosomes Cancer, 1990 Jul;2:159-62; Brose MS et al. Cancer Res, 2002 Dec;62:6997-7000; Bacher U et al. Blood, 2006 May;107:3847-53; Matsuda K et al. Blood, 2007 Jun;109:5477-80; Vaughn CP et al. Genes Chromosomes Cancer, 2011 May;50:307-12). This variant has also been reported to be de novo in an individual with features consistent with Noonan syndrome (Altmüller F et al. Eur J Hum Genet, 2017 Jun;25:823-831). In addition, in vitro functional studies demonstrated that the mutation increases downstream Ras signaling (Tyner JW et al. Blood, 2009 Feb;113:1749-55). Embryonic expression of this mutation led to embryonic lethality and cardiac developmental defects (You X et al. Front Cell Dev Biol, 2021 Feb;9:633661). Endogenous expression of this variant at weaning induced myeloproliferative disorder, and mice that died of a spectrum of hematologic malignancies (Li Q et al. Blood, 2011 Feb;117:2022-32). 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 alteration is interpreted as a disease-causing mutation. |
Clinical Genetics Laboratory, |
RCV000158980 | SCV005196770 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV001781333 | SCV005373898 | pathogenic | Noonan syndrome 6 | 2024-09-22 | criteria provided, single submitter | clinical testing | |
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 |