ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1269C>G (p.Asn423Lys) (rs138459502)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159188 SCV000209134 likely pathogenic not provided 2011-12-20 criteria provided, single submitter clinical testing The N423K missense change has not been reported previously as a disease-causing mutation nor as a benign polymorphism to our knowledge. The N423K missense change is non-conservative as a neutral residue (Asn) is replaced by a positively charged residue (Lys). The position at which this substitution occurs is conserved in the SOS1 protein, but not in related proteins. Two other missense changes in neighboring codons (M422V and E424K) have been reported as possible pathogenic variants (Lepri et al., 2011). The vast majority of missense changes in SOS1 are pathogenic; however, a small number of coding polymorphisms have been identified in this gene. Therefore, N423K is a candidate for a disease-causing mutation; however, further studies are required before this can be definitively determined. The variant is found in NOONAN panel(s).
Invitae RCV000556655 SCV000659126 uncertain significance Rasopathy 2017-03-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 423 of the SOS1 protein (p.Asn423Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs138459502, ExAC 0.01%) but has not been reported in the literature in individuals with a SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 40666). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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