ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2966G>A (p.Arg989Lys) (rs202043599)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038541 SCV000062219 likely benign not specified 2018-02-23 criteria provided, single submitter clinical testing p.Arg989Lys in exon 19 of SOS1: This variant is not expected to have clinical si gnificance because the arginine (Arg) residue at position 989 is not conserved t hrough species, with 7 mammals (lesser egyptiam jerboa, naked mole rat, alpaca, bactrian camel, hedgehog, cape elephant shrew and manatee) having a lysine (Lys) at this position. It has been identified in 7/62190 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202 043599).
GeneDx RCV000586941 SCV000518866 likely benign not provided 2016-11-01 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.
Integrated Genetics/Laboratory Corporation of America RCV000038541 SCV000698629 likely benign not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: SOS1 c.2966G>A (p.Arg989Lys) results in a 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. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 246376 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7-fold over the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2966G>A has been reported in the literature in an individual affected with Ependymoma without strong evidence for causality (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two cited the variant as likely benign and two cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000654932 SCV000776838 uncertain significance Rasopathy 2017-08-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 989 of the SOS1 protein (p.Arg989Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs202043599, ExAC 0.01%). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 45357). 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 lysine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586941 SCV000860417 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001138300 SCV001298342 uncertain significance Noonan syndrome 4 2018-01-12 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.
Illumina Clinical Services Laboratory,Illumina RCV001143052 SCV001303549 likely benign Gingival fibromatosis 1 2018-01-12 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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.