ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1300G>A (p.Gly434Arg)

dbSNP: rs397517148
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038514 SCV000062192 pathogenic Noonan syndrome 2012-11-13 criteria provided, single submitter clinical testing The 1300G>A (Gly434Arg) variant in SOS1 has previously been identified as a de n ovo variant in one individual with sporadic clinical features of Noonan syndrome (Zenker 2007). In addition, a different nucleotide change that causes the same amino acid change at this location (1300G>C) has also been associated with the c linical features of Noonan syndrome and was shown to have occurred de novo (Robe rts 2007). Therefore, this variant is highly likely to be pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626886 SCV000747589 pathogenic Pulmonic stenosis; Short stature; Ptosis; Abnormal sternum morphology 2017-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781878 SCV000920259 pathogenic RASopathy 2018-06-11 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1300G>A (p.Gly434Arg) results in a non-conservative critical amino acid change located in the membrane-binding surface of the Pleckstrin Homology (PH) domain of the encoded protein sequence (Lepri_2011). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245568 control chromosomes (gnomAD). The variant, c.1300G>A, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Alfieri_2014, Binder_2012, Lepri_2011, Roberts_2007). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, and demonstrated an increased capacity to induce ERK activation in starved cells (Smith_2013). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as Pathogenic.
Blueprint Genetics RCV000788323 SCV000927387 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856735 SCV000999282 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Invitae RCV000781878 SCV001210945 pathogenic RASopathy 2022-07-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). 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 SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40672). This missense change has been observed in individuals with RASopathy spectrum disorders (PMID: 17143285, 17586837, 20186801, 21387466). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 434 of the SOS1 protein (p.Gly434Arg).
Illumina Laboratory Services, Illumina RCV001270835 SCV001451603 pathogenic Noonan syndrome 4 2019-03-05 criteria provided, single submitter clinical testing The SOS1 c.1300G>A (p.Gly434Arg) variant is a missense variant that has been reported in at least two studies, in which it is found in a heterozygous state in three individuals with Noonan syndrome (Zenker et al. 2007; Lepri et al. 2011). Another variant that results in p.Gly434Arg has also been reported in at least three studies, in a total of five individuals with Noonan syndrome including a mother and son (Roberts et al. 2007; Alfieri et al. 2013; Koh et al. 2019). Phenotypes included cryptorchidism, pulmonary stenosis, short stature, mild hypertelorism, cubitus valgus, shield chest, and pectus deformity (Roberts et al. 2007; Koh et al. 2019). The p.Gly434Arg variant has been reported in a de novo state in at least two individuals (Zenker et al. 2007; Koh et al. 2019). Control data are unavailable for the p.Gly434Arg variant and it is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Gly434Arg variant is classified as pathogenic for Noonan syndrome.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526663 SCV001737095 pathogenic Fetal cystic hygroma criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813286 SCV002060440 likely pathogenic Noonan syndrome and Noonan-related syndrome 2018-12-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV002054543 SCV002495969 pathogenic Fibromatosis, gingival, 1; Noonan syndrome 4 2021-03-30 criteria provided, single submitter clinical testing SOS1 NM_005633.3 exon 10 p.Gly434Arg (c.1300G>A): This variant has been reported in the literature in at least 3 individuals with a RASopathy, at least 1 of whom was identified to have this variant de novo (Zenker 2007 PMID:17586837, Lepri 2011 PMID:21387466). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40672). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will impact the protein (Smith 2013 PMID:23487764). Of note, other variants that result in the same amino acid change as well as at this position have also been reported in the literature in association with disease (c.1300G>C Roberts 2007 PMID:17143285, p.Gly434Lys Lepri 2011 PMID:21387466) supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic.
Ambry Genetics RCV002381284 SCV002689847 pathogenic Cardiovascular phenotype 2022-03-25 criteria provided, single submitter clinical testing The p.G434R pathogenic mutation (also known as c.1300G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1300. The glycine at codon 434 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple Noonan syndrome cohorts; including a de novo occurrence (Roberts AE et al. Nat Genet, 2007 Jan;39:70-4; Zenker M et al. J Med Genet, 2007 Oct;44:651-6; Alfieri P et al. Am J Med Genet A, 2014 Apr;164A:934-42; Koh AL et al. Mol Genet Genomic Med, 2019 04;7:e00581; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337). In addition, this alteration may have an impact on protein function (Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Genome-Nilou Lab RCV001270835 SCV002763433 likely pathogenic Noonan syndrome 4 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001270835 SCV003843226 pathogenic Noonan syndrome 4 2021-04-01 criteria provided, single submitter clinical testing

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