Submissions for variant NM_005633.4(SOS1):c.2536G>A (p.Glu846Lys)

dbSNP: rs397517159

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000038535	SCV000616387	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.2536G>A (p.Glu846Lys) 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 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys variant may impact the protein (PP3). 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 to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). 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, Mass General Brigham Personalized Medicine	RCV000038535	SCV000062213	pathogenic	Noonan syndrome	2012-06-06	criteria provided, single submitter	clinical testing	The Glu846Lys variant in SOS1 has previously been identified in many individuals with clinical features of Noonan syndrome (Lepri 2011, Marco Tartaglia 2007, Ne umann 2009, Roberts 2007, Zenker 2007). This variant has shown segregation consi stent with pathogenicity in a familial case and to have occurred de novo in spor adic cases. In summary, this variant meets our criteria to be classified as path ogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000207492	SCV000209077	pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant results in increased EGF-evoked ERK activation and sustained endogenous RAS activation (Roberts et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26918529, 23673306, 24803665, 22555271, 21387466, 21041952, 18854871, 19077116, 17586837, 18651097, 17143282, 28492532, 30055033, 30417923, 31263281, 32753483, 33042901, 34184824, 30732632, 33219052, 17143285)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207492	SCV000263044	pathogenic	not provided	2015-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471633	SCV000553278	pathogenic	RASopathy	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 846 of the SOS1 protein (p.Glu846Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 18651097, 18854871, 19077116, 21387466, 23673306). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40706). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. Experimental studies have shown that this missense change affects SOS1 function (PMID: 17143285, 21041952). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000207492	SCV000884560	pathogenic	not provided	2017-11-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763085	SCV000893611	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000471633	SCV000920261	pathogenic	RASopathy	2018-06-18	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.2536G>A (p.Glu846Lys) results in a conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277182 control chromosomes (gnomAD and publication). The variant, c.2536G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Zenker_2007, Tartaglia_2007, Lepri_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. Authors found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts (Chen_2010). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000207492	SCV001446964	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000207492	SCV002021901	pathogenic	not provided	2021-07-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813296	SCV002060942	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453285	SCV002739312	pathogenic	Cardiovascular phenotype	2016-04-15	criteria provided, single submitter	clinical testing	The p.E846K pathogenic mutation (also known as c.2536G>A), located in coding exon 16 of the SOS1 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia M, Nat. Genet. 2007 Jan; 39(1):75-9; Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4; Zenker M, J. Med. Genet. 2007 Oct; 44(10):651-6; Neumann TE, Eur. J. Hum. Genet. 2009 Apr; 17(4):420-5; Lepri F, Hum. Mutat. 2011 Jul; 32(7):760-72; Li K, J Cutan Med Surg 2013 May-Jun; 17(3):212-8). In addition, functional studies demonstrated that this alteration resulted in increased RAS-ERK activation (Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4). Based on the supporting evidence, p.E846K is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003421942	SCV004117865	pathogenic	SOS1-related disorder	2023-02-17	criteria provided, single submitter	clinical testing	The SOS1 c.2536G>A variant is predicted to result in the amino acid substitution p.Glu846Lys. This variant has previously been reported in individuals with Noonan syndrome and in at least one report to have arose de novo (see for example - Tartaglia et al 2007. PubMed ID: 17143282; Li et al. 2013. PubMed ID: 23673306; Hakami et al. 2016. PubMed ID: 26918529). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Roberts et al. 2007. PubMed ID: 17143285). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786289	SCV005399079	pathogenic	Noonan syndrome 4	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 4 (MIM#610733) (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RasGEF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign ||||