ClinVar Genomic variation as it relates to human health

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.

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.

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.

Identified in an individual with Noonan syndrome who also had a de novo pathogenic variant in the RAF1 gene, likely the causative variant (Longoni et al., 2010); and identified in another individual with features of Noonan syndrome but was inherited from an asymptomatic parent (Lepri et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are commonly considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25712082, 22585553, 24803665, 20683980, 21387466, 29752777, 34426522, 29493581, 17143282, 12628188, 20648242)

proposed classification - variant undergoing re-assessment, contact laboratory

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.

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.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 497 of the SOS1 protein (p.Arg497Gln). This variant is present in population databases (rs371314838, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Noonan syndrome (PMID: 20683980, 21387466). ClinVar contains an entry for this variant (Variation ID: 45348). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SOS1 function (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.

The p.R497Q variant (also known as c.1490G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1490. The arginine at codon 497 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a proband with Noonan syndrome who also had a de novo mutation in the RAF1 gene, and ectodermal findings atypical for RAF1 mutations. The proband's father and paternal grandfather, who also had the p.R497Q variant, were reported to not have Noonan syndrome; however, they displayed similar mild ectodermal findings (Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). This variant was also detected in an individual from a cohort with Noonan syndrome or related features where it was inherited from a reportedly unaffected parent, and in an individual with cryptorchidism; however, details were limited (Lepri F et al. Hum. Mutat., 2011 Jul;32:760-72; Rodríguez F et al. Andrology, 2018 07;6:579-584). Functional assays have indicated this variant to result in activation of the Rac1 pathway, but not of the Ras-Erk pathway (Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.