ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.985G>A (p.Glu329Lys) (rs756679265)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654955 SCV000776863 uncertain significance Rasopathy 2018-10-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 329 of the SOS1 protein (p.Glu329Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs756679265, ExAC 0.009%). This variant has not been reported in the literature in individuals with SOS1-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Institute of Human Genetics,University of Goettingen RCV000991072 SCV001132606 uncertain significance Noonan syndrome 4 2019-12-23 criteria provided, single submitter clinical testing Although the SOS1-Variant has a pathogenic computational verdict due to 10 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and REVEL vs 2 benign predictions from DEOGEN2 and SIFT, is listed in gnomAD at a very low population frequency (1/251070 alleles) and located in the DH-domain of the SOS1-protein, our patient presented with symptoms of a CHARGE-Syndrome (although no pathogenic mutations in CHD7, SEMA3E, TBX1, TBX22 could be detected). At this moment there is no indication from the present literature, that this variant is pathogenic, but also vice versa there is no indication, that this variant is a mere rare polymorphism. Thus, we considered this variant to be a variant of unknown significance, with possibly benign character.

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