ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.508A>G (p.Lys170Glu) (rs397517172)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000038560 SCV000616383 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466). In vitro functional studies provide some evidence that the p.Lys170Glu variant may impact protein function (PS3; PMID 21784453, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Lys170Glu variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PM6, PS3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038560 SCV000062238 pathogenic Noonan syndrome 2011-09-26 criteria provided, single submitter clinical testing The Lys170Glu has been reported in four individuals with clinical features of No onan syndrome (Ko 2008, Lee 2011, Lepri 2011). In addition, this variant has occ urred de novo in two individuals (Ko 2008, LMM unpublished data). Furthermore, functional data indicates that this variant leads to gain-of-function (Lee 2011) , which is an established pathogenic mechanism in Noonan syndrome. In summary, t his variant meets our criteria to be classified as pathogenic (http://pcpgm.part ners.org/LMM).
GeneDx RCV000157689 SCV000209094 pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing The K170E missense variant in the SOS1 gene has been reported previously in association with Noonan syndrome (Ko et al., 2008; Lee et al., 2011; Smith et al., 2013). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K170E 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies confirm that K170E induces ERK activation and increases the pERK exchange rate compared to wildtype (Smith et al., 2013).
Invitae RCV000476014 SCV000553270 pathogenic Rasopathy 2019-07-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 170 of the SOS1 protein (p.Lys170Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (rs397517172, ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 19020799, 19953625, 21387466). ClinVar contains an entry for this variant (Variation ID: 40651). Experimental studies have shown that this missense change results in increased RAS and ERK activation in cell culture (PMID: 21784453). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624105 SCV000741316 pathogenic Inborn genetic diseases 2016-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002150 SCV001160005 pathogenic not specified 2018-09-25 criteria provided, single submitter clinical testing The SOS1 c.508A>G; p.Lys170Glu variant (rs397517172), is reported in the literature in multiple individuals affected with Noonan syndrome (Denayer 2010, Ko 2008, Lepri 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40651), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein shows increased activation of Ras and ERK, due to structural changes in the autoinhibitory HF domain (Lee 2011, Smith 2013). The lysine at codon 170 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Lys170Glu variant is considered to be pathogenic. References: Denayer E et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010 Mar;49(3):242-52. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Lee BH et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec;159(6):1029-35. Lepri F et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. Smith MJ et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9.
Integrated Genetics/Laboratory Corporation of America RCV000476014 SCV001363487 pathogenic Rasopathy 2019-04-15 criteria provided, single submitter clinical testing Variant summary: SOS1 c.508A>G (p.Lys170Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). c.508A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions, several patients having the variant as a de novo occurrence (van Trier_2015, Lepri_2011, Denayer_2010, Ko_2008). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in increased ERK and RAS activation and increased exchange activity compared to wild-type (Smith_2013, Lee_2011). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Furthermore, one submission from an expert panel (ClinGen) also cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157689 SCV000207673 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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