ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1655G>T (p.Arg552Met) (rs397517154)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000787996 SCV000927025 likely pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID: 21387466). his AA residue has been specified as a hotspot for variation. 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Met 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3.
GeneDx RCV000484403 SCV000565586 pathogenic not provided 2017-02-09 criteria provided, single submitter clinical testing The R552M variant has been published previously in association with Noonan syndrome (Lepri et al., 2011). The variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). R552M 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R552 residue has been shown to be critical to the stability of the SOS1 protein (Lepri et al., 2011). Missense variants in the same residue (R552G/W/T/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. In summary, we consider this variant to be pathogenic.
Invitae RCV000685882 SCV000813382 uncertain significance Rasopathy 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 552 of the SOS1 protein (p.Arg552Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Noonan syndrome (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 40681). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Arg552 amino acid residue in SOS1 has been determined to be clinically significant (PMID: 21387466, 17143282, 23487764, 18854871, 17586837, 25073238, 21340158). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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