ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1300G>A (p.Gly434Arg) (rs397517148)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-04-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 434 of the SOS1 protein (p.Gly434Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with RASopathy spectrum disorders (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 40672). This variant has been reported to affect SOS1 protein function (PMID:23487764). A different variant (c.1300G>C) giving rise to the same protein effect observed here (p.Gly434Arg) has been determined to be pathogenic (PMID: 20186801, 17143285, 17586837). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,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

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