Submissions for variant NM_005633.4(SOS1):c.3391+3T>C

gnomAD frequency: 0.00001  dbSNP: rs761579423

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781880	SCV000920262	benign	not specified	2018-06-18	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.3391+3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 12 fold above 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.3391+3T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001552027	SCV001772641	likely benign	not provided	2021-01-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856201	SCV002108443	uncertain significance	RASopathy	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 21 of the SOS1 gene. It does not directly change the encoded amino acid sequence of the SOS1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs761579423, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 633430). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002458402	SCV002618266	uncertain significance	Cardiovascular phenotype	2022-08-31	criteria provided, single submitter	clinical testing	The c.3391+3T>C intronic variant results from a T to C substitution 3 nucleotides after coding exon 21 in the SOS1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.