ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3418T>A (p.Leu1140Ile) (rs375550588)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463473 SCV000553277 uncertain significance Rasopathy 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1140 of the SOS1 protein (p.Leu1140Ile). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs375550588, ExAC 0.02%). This variant has been reported in an individual of a Noonan syndrome study cohort (PMID: 21387466). 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 with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Phosphorus, Inc. RCV000577966 SCV000679915 uncertain significance Noonan syndrome 4 2017-08-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000592644 SCV000709736 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 7/121778 Europeans in gnomad-2:39214706 A / T, identified in 1 individual with possible Noonan syndrome, but classified as a VUS Lepri et al., 2011, benign by prediction tools
Integrated Genetics/Laboratory Corporation of America RCV000592644 SCV001363486 uncertain significance not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3418T>A (p.Leu1140Ile) results in a conservative amino acid change located in the SH3-binding motifs (Lepri_2011) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 243008 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3418T>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Lepri_2011, Ceyhan-Birsoy_2018, Shapiro_2017). These reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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