ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3269C>T (p.Pro1090Leu) (rs730881034)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000192568 SCV000209082 likely benign not specified 2017-12-13 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.
Genetic Services Laboratory, University of Chicago RCV000192568 SCV000249011 uncertain significance not specified 2015-05-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000192568 SCV000272447 uncertain significance not specified 2015-11-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Pro1090Leu va riant in SOS1 has not been previously reported in individuals with a RASopathy, but has been identified in 11/66720 European chromosomes including one homozygou s individual and 6/16512 South Asian chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs730881034). Computational pr ediction tools and conservation analysis do not provide strong support for or ag ainst an impact to the protein. In summary, while the clinical significance of the p.Pro1090Leu variant is uncertain, its frequency suggests that it is more li kely to be benign.
Integrated Genetics/Laboratory Corporation of America RCV000192568 SCV000698631 likely benign not specified 2019-11-21 criteria provided, single submitter clinical testing Variant Summary: SOS1 c.3269C>T (p.Pro1090Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251006 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 13 fold of 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. c.3269C>T has been reported in the literature in a 4 m/o patient who presented with GERD, chylous pleural effusion, chronic lung disease and astigmatism (Bhoj_2016). The final diagnosis of the patient is reported as "undiagnosed" with a variant classification as "likely benign" and a "negative" diagnosis (Bhoj_2016). Therefore, this report does not provide an unequivocal conclusion about the 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 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000819933 SCV000960621 uncertain significance Rasopathy 2019-05-09 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1090 of the SOS1 protein (p.Pro1090Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs730881034, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 40722). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000997119 SCV001152238 likely benign not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001143048 SCV001303545 likely benign Gingival fibromatosis 1 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 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.
Illumina Clinical Services Laboratory,Illumina RCV001143049 SCV001303546 uncertain significance Noonan syndrome 4 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.

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