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 | likely benign | Cardiovascular phenotype | 2024-09-30 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Labcorp Genetics |
RCV002542975 | SCV003497355 | likely benign | RASopathy | 2024-12-23 | criteria provided, single submitter | clinical testing |