ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2536G>A (p.Glu846Lys) (rs397517159)

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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 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, Partners HealthCare 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 2018-10-30 criteria provided, single submitter clinical testing The E846K variant in the SOS1 gene has been reported previously in association with Noonan syndrome, including de novo occurrences (Tartaglia et al., 2007; Li et al., 2013; Lepri et al., 2011; Roberts et al, 2007). The E846K variant is not observed in large population cohorts (Lek et al., 2016). The E846K 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 within the CDC25 domain containing the catalytic site of the SOS1 protein. Functional studies of the E846K variant have demonstrated that it results in increased EGF-evoked ERK activation (Roberts et al., 2007). We interpret E846K as a pathogenic variant.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207492 SCV000263044 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
Invitae RCV000471633 SCV000553278 pathogenic Rasopathy 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 846 of the SOS1 protein (p.Glu846Lys). 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 is one of the most common SOS1 variants observed in individuals affected with Noonan syndrome (PMID: 17143282, 17143285, 19077116, 21387466, 18651097, 18854871). In several of these individuals the variant arose de novo (PMID: 23673306, 17586837). Overall, it is estimated to account for ~10% of SOS1 variants in affected individuals (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 40706). Experimental studies in both cell culture and a knock-in mouse model have shown that this missense change results in increased SOS1 activity, resulting in higher levels of RAS/MAPK pathway signaling (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 Gingival fibromatosis 1; Noonan syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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