ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.3997T>C (p.Ter1333Arg)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001066044 SCV001231037 uncertain significance Noonan syndrome 9 2019-10-02 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the SOS2 gene (p.*1333Argext*2). While this is not anticipated to result in nonsense mediated decay, it extends the protein by an additional 2 amino acids. This variant is present in population databases (rs142666803, ExAC 0.02%). This variant has not been reported in the literature in individuals with SOS2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193656 SCV001362635 uncertain significance not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: SOS2 c.3997T>C (p.X1333ArgextX2) changes the termination codon and is predicted to lead to an extended protein with two additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 5.2e-05 in 250822 control chromosomes (gnomAD). The observed variant frequency is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. Activating mutations in SOS2 have been reported in patients with Noonan syndrome, however, the relevance of stop-codon read through variants on the associated mechanism and/or pathophysiology of Noonan syndrome is not clear. c.3997T>C has been reported in the literature in at-least one individual from a family reportedly affected with Brugada syndrome (Molina_2019). This report does not provide unequivocal conclusions about association of the variant with either Brugada syndrome or Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261128 SCV001438535 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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