ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3286T>A (p.Ser1096Thr) (rs376722127)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547835 SCV000659145 uncertain significance Rasopathy 2017-03-11 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1096 of the SOS1 protein (p.Ser1096Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs376722127, ExAC 0.02%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 22589294). 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, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000780744 SCV000918256 uncertain significance not specified 2018-05-07 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3286T>A (p.Ser1096Thr) results in a conservative amino acid change in 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 9.8e-05 in 246072 control chromosomes. The observed variant frequency is approximately 3.25 fold above the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), suggesting that the variant might be benign. The variant, c.3286T>A, has not been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions but was reported in patients with osteosarcoma and HBOC (Zhang_2015, Maxwell_2016) and in one family with idiopathic HCM where it segregated with disease in 2/3 individuals (Kaski_2012). 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. 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.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761177 SCV000891093 uncertain significance B-Lymphoblastic Leukemia/Lymphoma with Intrachromosomal Amplification of Chromosome 21 2017-05-23 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.