ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.322G>A (p.Glu108Lys) (rs397517164)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000038546 SCV000616437 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID: 17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID: 17143282, 23487764). This variant was absent from large population studies (PM2; ExAC, The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS3, PM6, PS4_Moderate, PM2, PP2.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038546 SCV000062224 likely pathogenic Noonan syndrome 2013-12-17 criteria provided, single submitter clinical testing The Glu108Lys variant in SOS1 has been reported in 6 individuals with clinical f eatures of Noonan syndrome and segregated with disease in 1 affected relative (T artaglia 2007, Lepri 2011, LMM unpublished data). This variant has not been iden tified in large population studies. Functional studies have shown that the Glu10 8Lys variant leads to increased activation of SOS1 protein (Gureasko 2010, Smith 2013, Saliba 2013, Findlay 2013). However, these in vitro assays may not accura tely represent biological function. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance.
GeneDx RCV000159144 SCV000209088 pathogenic not provided 2017-08-10 criteria provided, single submitter clinical testing The E108K pathogenic variant in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007; Lepri et al., 2011). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. However, the E108K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, functional studies demonstrate that the E108K variant, which is located in the histone fold domain of the encoded protein, disrupts protein activation and membrane assocation (Gureasko et al., 2010; Saliba et al., 2014). We interpret E108K as a pathogenic variant, consistent with global developmental delay, learning disability, pulmonic valve stenosis, pectus excavatum, hypertelorism, and easy bruising.
Invitae RCV000537356 SCV000659144 pathogenic Rasopathy 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 108 of the SOS1 protein (p.Glu108Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in four unrelated individuals with Noonan Syndrome (PMID: 21387466, 17143282). ClinVar contains an entry for this variant (Variation ID: 40649). Experimental studies have demonstrated that this missense change results in increased activation of the SOS1 protein (PMID: 20133692, 20133694, 23452850, 24270602). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000537356 SCV001821270 pathogenic Rasopathy 2021-08-15 criteria provided, single submitter clinical testing Variant summary: SOS1 c.322G>A (p.Glu108Lys) results in a conservative amino acid change located in the Histone H2A/H2B/H3 domain (IPR007125) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251142 control chromosomes. c.322G>A has been reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2007, Lepri_2011, Kauffman_2020). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of pERK (i.e., increased RAS/MAPK output) via increased membrane association (example, Smith_2013, Gureasko_2009). Two clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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