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

gnomAD frequency: 0.00003  dbSNP: rs374061873

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 ://evs.gs.washington.edu; 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 In addition, this variant was not identified in an unaffected father (LMM unpublished data).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 Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654962	SCV000776872	uncertain significance	RASopathy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 185 of the NRAS protein (p.Pro185Ser). This variant is present in population databases (rs374061873, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 179025). 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 not expected to disrupt NRAS protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155806	SCV002041644	likely benign	not specified	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: NRAS c.553C>T (p.Pro185Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251444 control chromosomes. The observed variant frequency is approximately 27.044 fold of the estimated maximal expected allele frequency for a pathogenic variant in NRAS causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.553C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261093	SCV001438495	likely benign	Noonan syndrome		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945240	SCV004762729	uncertain significance	NRAS-related disorder	2023-12-11	no assertion criteria provided	clinical testing	The NRAS c.553C>T variant is predicted to result in the amino acid substitution p.Pro185Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115251173-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.