ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1490G>A (p.Arg497Gln) (rs371314838)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000801491 SCV001424738 likely benign Rasopathy 2020-07-02 reviewed by expert panel curation The c.1490G>A (p.Arg497Gln) variant in SOS1 was present in 0.0113% (4/35392) of Latino chromosomes in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in 1 proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). Of note, it has also been observed in other probands with disparate phenotypes and their reportedly unaffected parents; however, these individuals were not well-phenotyped and, therefore, do not meet current requirements for BS2 (BS2 not met; PMID:21387466, Otto von Guericke University Magdeburg, GeneDx, Partners Laboratory for Molecular Medicine, Integrated Genetics, and Baylor Genetics internal data; ClinVar SCV000209114.12, SCV000062197.7, SCV001361139.1). In vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). Although this variant occurs in a location defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1, expert judgement was used to classify this variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): BS3, BP5.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038519 SCV000062197 uncertain significance not specified 2014-10-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000656980 SCV000209114 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing The R497Q variant in the SOS1 gene has been reported previously in an individual with Noonan syndrome (Longoni et al., 2010). However, this individual also had a de novo pathogenic variant in the RAF1 gene, which was felt to likely be causative for the Noonan syndrome phenotype. It was suggested that the R497Q variant may be contributing the cutaneous features in the family as the variant was also found in this individual’s father and grandfather, who were noted to have mild ectodermal findings (Longoni et al., 2010). The R497Q variant was reported in another publication in an individual with features of Noonan syndrome, but was inherited from an asymptomatic parent (Lepri et al., 2011). The R497Q variant is observed in 2/18,830 (0.011%) alleles from individuals of East Asian background and 16/276,456 (0.0058%) total alleles in large population cohorts (Lek et al., 2016). The R497Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The R497Q variant is located in the Pleckstrin homology domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies demonstrate that R497Q does not affect the Ras-Erk pathway but does activate Jnk signaling in the Rac1 pathway (Longoni et al., 2010). We interpret R497Q as a variant of uncertain significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000156991 SCV000890935 likely benign Noonan syndrome 2020-09-23 criteria provided, single submitter clinical testing The c.1490G>A missense variant has a frequency of 0.00005677 (16 of 281,850 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0001130 (4 of 35,392) in the Latino subpopulation (http://gnomad.broadinstitute.org). Although multiple lines of computational evidence suggest a deleterious effect on the gene or gene product (PP3), in vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). This variant has been observed in one proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). This variant has been classified as likely benign by the ClinGen RASopathy Variant Curation Expert Panel with additional unpublished patient data (SCV001424738.1). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BS3, BP5.
Invitae RCV000801491 SCV000941268 uncertain significance Rasopathy 2020-07-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 497 of the SOS1 protein (p.Arg497Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs371314838, ExAC 0.01%). This variant has been reported in individuals affected with suspected Noonan syndrome (PMID: 20683980, 21387466), however one of these individuals also carried a de novo variant in RAF1 (PMID: 20683980). ClinVar contains an entry for this variant (Variation ID: 45348). Experimental studies have shown that this missense change results in up-regulation of JNK phosphorylation, but not ERK phosphorylation, which is more traditionally associated with Noonan syndrome (PMID: 20683980, 25712082). 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.
Mendelics RCV000986624 SCV001135666 uncertain significance Noonan syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656980 SCV001152239 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001143160 SCV001303663 uncertain significance Gingival fibromatosis 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001143161 SCV001303664 uncertain significance Noonan syndrome 4 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038519 SCV001361139 likely benign not specified 2020-07-08 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1490G>A (p.Arg497Gln) results in a conservative amino acid change located in the Pleckstrin homology domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250470 control chromosomes. The observed variant frequency is approximately 2-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 benign. c.1490G>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (e.g. Lepri_2011, Longoni_2010). In one family the variant was indicated to have been inherited from an unaffected parent (Lepri_2011). A similar inheritance from a carrier mother has been observed at-least once at our laboratory. In another family, the variant co-occurred in a patient with a de novo pathogenic RAF1 variant (c.781C>T, p.Pro261Ser). The patient's father and paternal grandfather also carried the variant of interest and authors indicated that the variant may have contributed to cutaneous anomalies that were observed in these family members (Longoni_2010). Another study (Rodriguez_2018) reported the variant in a patient affected with isolated cryptorchidism. Experimental evidence evaluating an impact on protein function demonstrated the variant does not induce Erk1 phosphorylation above the level of the wild type. Evaluating Rac1 pathway signal transduction, the authors determined the variant activates Jnk however, the implications of this finding in disease-manifestation are not conclusively established especially given that Jnk was not significantly activated under EGF stimulation in cells transfected with the known pathogenic p.M269R variant (Longoni_2010). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. However, recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of this variant as Likely Benign (personal communication, June 2020). Based on the evidence outlined above, the variant was re-classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156991 SCV000206714 uncertain significance Noonan syndrome 2013-02-19 no assertion criteria provided clinical testing

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