ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.3490-13_3490-12dup (rs10658395)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533674 SCV000656024 benign Noonan syndrome 9 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000604410 SCV000731090 benign not specified 2017-11-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000604410 SCV001361616 benign not specified 2019-08-19 criteria provided, single submitter clinical testing Variant summary: SOS2 c.3490-5_3490-4dupTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.038 in 103896 control chromosomes in the gnomAD database (exomes dataset), including 41 homozygotes. The observed variant frequency is approximately 15000 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. To our knowledge, no occurrence of c.3490-5_3490-4dupTT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

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