ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.553C>T (p.Pro185Ser) (rs374061873)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155806 SCV000205517 likely benign not specified 2014-07-15 criteria provided, single submitter clinical testing Pro185Ser in exon 5 of NRAS: This variant has not been previously reported in in dividuals with clinical features of Noonan syndrome, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http ://; dbSNP rs374061873). In addition, this variant was not identified in an unaffected father (LMM unpublished data). Pro185 is not well co nserved across species and the change to Serine (ser) has been seen in multiple mammals (shrew, opossum, and Tasmanian devil) and in many other more evolutionar ily distant species, suggesting that this change might be tolerated. Other compu tational prediction tools suggest that this variant may not impact the protein. In summary, the Pro185Ser variant is classified as likely benign based on its la ck of conservation and presence in an unaffected parent.
GeneDx RCV000155806 SCV000208916 likely benign not specified 2013-06-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000373742 SCV000347394 uncertain significance Noonan syndrome 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000654962 SCV000776872 uncertain significance Rasopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 185 of the NRAS protein (p.Pro185Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs374061873, ExAC 0.009%). This variant has not been reported in the literature in individuals with NRAS-related disease. ClinVar contains an entry for this variant (Variation ID: 179025). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.