ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1642A>C (p.Ser548Arg) (rs397517149)

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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 RCV000038515 SCV000616385 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 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.Ser548Arg 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, PS3 PS2_VeryStrong.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038515 SCV000062193 pathogenic Noonan syndrome 2006-10-28 criteria provided, single submitter clinical testing The p.Ser548Arg variant in SOS1 has been reported in >10 individuals with clinic al features of Noonan syndrome and was de novo in at least 2 of these individual s (Tartaglia 2007, Roberts 2007, Lepri 2011, LMM unpublished data). It was absen t from large population studies. In vitro functional studies provide some eviden ce that the p.Ser548Arg variant may impact protein function (Smith et al., 2013) . In summary, this variant meets our criteria to be classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153986 SCV000203611 pathogenic not provided 2014-01-07 criteria provided, single submitter clinical testing
GeneDx RCV000153986 SCV000209115 pathogenic not provided 2017-09-18 criteria provided, single submitter clinical testing The S548R variant in the SOS1 gene has been reported previously in patients with Noonan syndrome, including de novo occurrences (Tartaglia et al., 2007; Roberts et al., 2007; Lepri et al., 2011; Simsek-Kiper et al., 2013; Hakami et al, 2016). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S548R is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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 of the S548R variant have shown that it results in increased RAS exchange activity (Smith et al., 2013). In addition, another nucleotide change (c.1644 T>G) at the same position also leading to the S548R missense change and missense variants in nearby residues (T549K, L550P, R552G/T/K/M/S/S) have been reported in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Ambry Genetics RCV000623399 SCV000741658 likely pathogenic Inborn genetic diseases 2016-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000654915 SCV000776821 pathogenic Rasopathy 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 548 of the SOS1 protein (p.Ser548Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 17143282, 20186801, 21387466, 22420426, 17143285, 19077116, 19020799, 22465605). Additionally, the same amino acid change caused by a different nucleotide change (c.1644T>G) has also been reported in several individuals affected with Noonan syndrome (PMID: 20607846, 23885229). ClinVar contains an entry for this variant (Variation ID: 40678). Experimental studies have shown that this missense change increases the activation of the SOS1 protein (PMID: 23487764, 20133692). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763087 SCV000893613 pathogenic Gingival fibromatosis 1; Noonan syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000153986 SCV000927567 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing

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