Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000587119 | SCV000209085 | uncertain significance | not provided | 2018-07-25 | criteria provided, single submitter | clinical testing | The c.3412 A>G (I1138V ) variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/268,480 global alleles (0.003%) in large population cohorts (Lek et al., 2016). Multiple in silico splice prediction programs predict that the c.3412 A>G substitution creates a cryptic splice donor site upstream of the canonical splice donor site in intron 22, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the actual effect of this sequence change in this individual is unknown.If expressed and translated, the I1138V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000722119 | SCV000698635 | uncertain significance | not specified | 2018-05-07 | criteria provided, single submitter | clinical testing | Variant summary: SOS1 c.3412A>G (p.Ile1138Val) 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 3e-05 in 268480 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions (3e-05 vs 3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3412A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have 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. |
| Labcorp Genetics |
RCV000697593 | SCV000826213 | likely benign | RASopathy | 2024-01-24 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000587119 | SCV002049617 | uncertain significance | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002453553 | SCV002612757 | uncertain significance | Cardiovascular phenotype | 2022-08-03 | criteria provided, single submitter | clinical testing | The p.I1138V variant (also known as c.3412A>G), located in coding exon 22 of the SOS1 gene, results from an A to G substitution at nucleotide position 3412. The isoleucine at codon 1138 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a Noonan syndrome cohort; however, clinical details were limited (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is well conserved in available 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. |
| Genome- |
RCV002467630 | SCV002763214 | uncertain significance | Noonan syndrome 4 | criteria provided, single submitter | clinical testing | ||
| Genome- |
RCV002467629 | SCV002763215 | uncertain significance | Fibromatosis, gingival, 1 | criteria provided, single submitter | clinical testing |