ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1655G>C (p.Arg552Thr) (rs397517154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208093 SCV000264232 pathogenic Noonan syndrome 2015-04-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626887 SCV000747590 pathogenic Abnormality of the aortic valve 2017-01-01 criteria provided, single submitter clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000208093 SCV000927026 pathogenic Noonan syndrome 2019-05-10 reviewed by expert panel curation The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The p.Arg552 residue has been defined as a hotspot by the RAS EP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Thr 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): PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3.
GeneDx RCV000159176 SCV000209121 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing The R552T variant has been previously reported in association with Noonan syndrome and with an allelic disorder, Noonan like/Multiple Giant Cell Lesion syndrome (Beneteau et al., 2009; Cizmarova et al., 2016) and has been observed de novo in patients tested at GeneDx. The R552T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R552T variant 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Pathogenic missense variants at this residue (R552G/M/K/S) and in nearby residues (S548R, T549K, L550P) have been reported in the Human Gene Mutation Database in association with Noonan Syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein
Invitae RCV000528274 SCV000659129 pathogenic Rasopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 552 of the SOS1 protein (p.Arg552Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with clinical features of Noonan syndrome (PMID: 19352411, 21387466, Laboratory of Molecular Medicine ClinVar entry, Invitae). ClinVar contains an entry for this variant (Variation ID: 40682). Multiple different missense substitution at this codon (p.Arg552Gly, p.Arg552Lys and p.Arg552Ser) have been determined to be pathogenic (PMID: 17143282, 23487764). This suggests that the arginine residue is critical for SOS1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208093 SCV000062201 pathogenic Noonan syndrome 2011-11-15 criteria provided, single submitter clinical testing The p.Arg552Thr variant in SOS1 has been identified in at least 5 individuals wi th clinical features of Noonan syndrome (Beneteau 2009, Lepri 2011, LMM unpublis hed data) and was absent from large population studies. Arginine (Arg) at positi on 552 is highly conserved in mammals, and evolutionarily distant species and ot her computational prediction tools suggest that this variant may impact the prot ein. Furthermore, several other amino acid changes at this position have been id entified in individuals with Noonan syndrome (p.Arg552Ser, p.Arg552Lys, p.Arg552 Met, p.Arg552Gly; Beneteau 2009, Lepri 2011), many of which occurred de novo, an d functional studies showed that another variant at the same position (p.Arg552G ly) caused increased and prolonged RAS activation (Tartaglia 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndro me in an autosomal dominant manner based upon absence from controls and supporti ng functional evidence.

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