ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.3729C>G (p.Asp1243Glu)

gnomAD frequency: 0.00007  dbSNP: rs730881026
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001703448 SCV000209062 likely benign not provided 2020-12-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30050098, 29907801)
Labcorp Genetics (formerly Invitae), Labcorp RCV000231740 SCV000288967 likely benign RASopathy 2023-11-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159118 SCV001361137 likely benign not specified 2024-02-15 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3729C>G (p.Asp1243Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 1613758 control chromosomes (gnomAD). The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. c.3729C>G has been reported in the literature in a prenatal sample with cystic hygroma without strong evidence for causality (Leach_2019). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 40734). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813302 SCV002060655 likely benign Noonan syndrome and Noonan-related syndrome 2016-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345265 SCV002621166 uncertain significance Cardiovascular phenotype 2022-04-12 criteria provided, single submitter clinical testing The p.D1243E variant (also known as c.3729C>G), located in coding exon 23 of the SOS1 gene, results from a C to G substitution at nucleotide position 3729. The aspartic acid at codon 1243 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in a prenatal subject with cystic hygroma (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is not well conserved in available vertebrate species, and glutamic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004742234 SCV005361771 uncertain significance SOS1-related disorder 2024-05-21 no assertion criteria provided clinical testing The SOS1 c.3729C>G variant is predicted to result in the amino acid substitution p.Asp1243Glu. This variant has been reported in a fetus with cystic hygroma; however, the authors suspected the variant was possibly benign (Table S2, Leach et al. 2019. PubMed ID: 29907801). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be pathogenic (Gelb et al. 2018. PubMed ID 29493581). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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