Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001564084 | SCV001472585 | uncertain significance | not provided | 2020-01-08 | criteria provided, single submitter | clinical testing | The SOS1 c.2225T>C; p.Ile742Thr variant (rs767494615), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the non-Finnish European population with an allele frequency of 0.010% (13/128840 alleles) in the Genome Aggregation Database. The isoleucine at codon 742 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ile742Thr variant is uncertain at this time. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290532 | SCV001478586 | likely benign | not specified | 2023-01-30 | criteria provided, single submitter | clinical testing | Variant summary: SOS1 c.2225T>C (p.Ile742Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251084 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2225T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and Uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. |
| Gene |
RCV001564084 | SCV001787188 | likely benign | not provided | 2021-03-09 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002430071 | SCV002727534 | uncertain significance | Cardiovascular phenotype | 2022-05-10 | criteria provided, single submitter | clinical testing | The p.I742T variant (also known as c.2225T>C), located in coding exon 14 of the SOS1 gene, results from a T to C substitution at nucleotide position 2225. The isoleucine at codon 742 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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. |
| Invitae | RCV002542975 | SCV003497355 | likely benign | RASopathy | 2024-01-04 | criteria provided, single submitter | clinical testing |