ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.233T>G (p.Phe78Cys) (rs201352584)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000514749 SCV000209092 uncertain significance not provided 2017-03-15 criteria provided, single submitter clinical testing The F78C variant of uncertain significance in the SOS1 gene has been published previously in an individual clinically diagnosed with Noonan syndrome (Rusu et al., 2014). And while F78C was identified in another individual with features of Noonan syndrome, that individual's mother also harbored the F78C missense change and was reportedly unaffected (Zenker et al., 2007). F78C is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F78C 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. Moreover, 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. This missense change is located in the N-terminal histone fold domain of the SOS1 protein and is predicted to interact with the Arginine residue at position 552, which is one of the most commonly mutated residues in SOS1. The substitution of this highly conserved Phenylalanine residue may structurally perturb the region of the domain and its interface with the helical linker (Lepri et al., 2011); however, supporting functional evidence is necessary to confirm this predicted effect.
Invitae RCV000460292 SCV000553271 uncertain significance Rasopathy 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 78 of the SOS1 protein (p.Phe78Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs201352584, ExAC 0.03%). This variant was identified in an individual affected with Noonan syndrome and this individual's reportedly unaffected mother (PMID: 17586837). ClinVar contains and entry for this variant (Variation ID: 40646) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514749 SCV000610271 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852537 SCV000995235 uncertain significance Ventricular tachycardia 2019-01-31 criteria provided, single submitter clinical testing
Mendelics RCV000986626 SCV001135668 uncertain significance Noonan syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
New York Genome Center RCV001281498 SCV001468807 uncertain significance Intellectual disability 2019-05-28 criteria provided, single submitter clinical testing The c.233T>G (p.Phe78Cys) variant identified in the SOS1 gene substitues a Phenylalnine for Cysteine at amino acid 78/1334 (coding exon 2/23). It is identified in gnomAD (44 heterozygotes, 0 homozygotes; allele frequency 1.56e-4) and ExAC (15 heterozygotes, 0 homozygotes; allele frequency: 1.24e-4. In silico algorithms predict this variant will be Deleterious (Provean; Score: -7.01) and Damaging (SIFT;Score: 0.00) to the function of the canonical transcript. The c.233T>G (p.Phe78Cys) variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:40646), and has been described in two individuals in the literature who met clinical criteriafor Noonan syndrome [doi:10.4183/aeb.2014.463; PMID: 17586837], one of which was inherited from a presumably unaffected parent [PMID: 17586837]. Given the lack of compelling information supporting the pathogenicity of the c.233T>G (p.Phe78Cys) variant identified in this indivudal, it is reported here as a Variant of Uncertain Significance.

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