ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2489A>G (p.Asn830Ser) (rs397517158)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159131 SCV000209075 uncertain significance not provided 2014-02-28 criteria provided, single submitter clinical testing p.Asn830Ser (AAC>AGC): c.2489 A>G in exon 15 of the SOS1 gene (NM_005633.3).The N830S missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. N830S is a conservative amino acid substitution with as Aspartic Acid and Serine are both neutral and polar residues. The N830S variant 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. The position at which this substitution occurs is highly conserved within the RAS-GEF domain of the protein but not in related proteins. The vast majority of missense changes in SOS1 are pathogenic; however, a small number of missense polymorphisms have been identified in this gene. Therefore, the N830S missense substitution is interpreted as a variant of unknown significance. The variant is found in NOONAN panel(s).
Invitae RCV000556321 SCV000659137 uncertain significance Rasopathy 2017-07-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 830 of the SOS1 protein (p.Asn830Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs397517158, ExAC 0.003%). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 181538). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Integrated Genetics/Laboratory Corporation of America RCV000781876 SCV000920255 uncertain significance not specified 2018-02-12 criteria provided, single submitter clinical testing Variant summary: SOS1 c.2489A>G (p.Asn830Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121166 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions (1.7e-05 vs 3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2489A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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