ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys) (rs397517154)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157017 SCV000206744 pathogenic Noonan syndrome 2012-05-25 no assertion criteria provided clinical testing
Blueprint Genetics RCV000159175 SCV000927595 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000157017 SCV000927028 pathogenic Noonan syndrome 2019-05-10 reviewed by expert panel curation The c.1655G>A (p.Arg552Lys) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837, 17143282, 30266093, 26686981). This variant has been detected in at least 7 independent occurrences with clinical features of a RASopathy (PS4; PMIDs: 17586837, 22420426, 28378436, 29037749, 25337068, 21387466, 21784453, 26918529, 21274610). In vitro functional studies provide some evidence that the p.Arg552Lys variant may impact protein function (PS3; PMID: 21784453). This residue has been defined as a PM1 hotspot by the RAS VCEP. 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). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg552Lys 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). 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): PS2_VeryStrong, PS4, PS3, PM1_Strong, PM2, PP2, PP3.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159175 SCV000336466 pathogenic not provided 2015-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000159175 SCV000209120 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing The R552K variant has been published as a pathogenic variant in association with Noonan syndrome, including de novo observations (Tartaglia et al., 2007; Lepri et al., 2011; Zenker et al., 2007). The R552K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R552K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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 nvariants at this residue (R552G/M/T/S/W) 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. In summary, based on the currently available information, this variant is pathogenic and consistent with the diagnosis of a RASopathy.
Integrated Genetics/Laboratory Corporation of America RCV000587705 SCV000698615 pathogenic Noonan syndrome 3 2017-02-20 criteria provided, single submitter clinical testing Variant summary: The SOS1 c.1655G>A (p.Arg552Lys) variant lies in the helical linker between the PH and Rem domains and is predicted to interact directly with the side chains of Asp140 and Asp169 in the histone domain of SOS1 (ref. 16). Disruption of this interaction could affect the relative orientation of the DH-PH unit and the Rem domain (Tartaglia_207). This change involves the alteration of a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a deleterious outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), but multiple publications cite the variant as causative in affected individuals including at least one de novo event and a mother-child affected duo. In addition, Arg552 appears to be a mutational hot-spot as other alterations of the same codon, such as p.Arg552Gly and p.Arg552Ser were identified as causative in multiple NS pts and were shown to increase in the basal level of active RAS and prolonged RAS activation after EGF stimulation in functional studies (Tartaglia_ 2007). Lastly, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157017 SCV000062200 pathogenic Noonan syndrome 2011-09-08 criteria provided, single submitter clinical testing The Arg552Lys variant in SOS1 has been reported in at least six individuals with clinical features of Noonan syndrome, four of whom were reported to have occurr ed de novo (Tartaglia 2007, Zenker 2007, Lepri 2011). In addition this variant was absent from 600 control chromosomes (Lepri 2011). Furthermore, different ami no acid changes at this location (Arg552Gly, Arg552Thr and Arg552Ser) have also been associated with clinical features of Noonan syndrome (Roberts 2007, Zenker 2007, Tartaglia 2007, Beneteau 2009, Lepri 2011). Protein modeling suggests that amino acid residue 552 plays an important role in structural formation of the p rotein (Lepri 2011). Therefore, it is highly likely that this variant is pathog enic. The presence of a heterozygous pathogenic variant in SOS1 is consistent wi th a diagnosis of Noonan syndrome, but this information should be reconciled wit h the complete clinical history of this individual.

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