Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000228572 | SCV000616434 | benign | RASopathy | 2017-04-03 | reviewed by expert panel | curation | The filtering allele frequency of the c.749T>C (p.Val250Ala) variant in the SOS1 gene is 0.089% for African chromosomes by the Exome Aggregation Consortium (15/10392 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). |
Laboratory for Molecular Medicine, |
RCV000038569 | SCV000062247 | uncertain significance | not specified | 2011-06-01 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Val250Ala varia nt has not been previously reported in the literature. However, this variant was identified in one other Black individual tested by our laboratory and that indi vidual's reportedly unaffected mother. This variant has now been identified in 2 /75 (2.7%) of Black probands tested by our laboratory. In addition, Val at posit ion 250 is not conserved across evolutionarily distinct species and computationa l analyses (PolyPhen2, SIFT, AlignGVGD) predict that this variant will not impac t the normal function of the protein. It should be noted that the sensitivity an d specificity of these computational programs has not been determined by our lab oratory. Therefore, the clinical significance of this variant cannot be determin ed conclusively at this time; however, based upon the arguments described above we would lean towards a more likely benign role. |
Gene |
RCV000157705 | SCV000209099 | benign | not provided | 2019-10-25 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostics Lab, |
RCV000038569 | SCV000263041 | uncertain significance | not specified | 2015-07-21 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000228572 | SCV000288969 | likely benign | RASopathy | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Center for Pediatric Genomic Medicine, |
RCV000157705 | SCV000511122 | likely benign | not provided | 2016-10-11 | criteria provided, single submitter | clinical testing | Converted during submission to Likely benign. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000038569 | SCV000698645 | likely benign | not specified | 2018-05-13 | criteria provided, single submitter | clinical testing | Variant summary: SOS1 c.749T>C (p.Val250Ala) results in a non-conservative amino acid change located in the Dbl homology (DH) domain of 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 0.00017 in 277018 control chromosomes. The observed variant frequency is approximately 6 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 benign. To our knowledge, no occurrence of c.749T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (2x), likely benign (3x), and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. |
ARUP Laboratories, |
RCV000157705 | SCV000884561 | uncertain significance | not provided | 2017-12-22 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813282 | SCV002060905 | uncertain significance | Noonan syndrome and Noonan-related syndrome | 2016-12-12 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002390135 | SCV002675055 | benign | Cardiovascular phenotype | 2019-03-28 | criteria provided, single submitter | clinical testing | This alteration is classified as 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. |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV000157705 | SCV000207694 | uncertain significance | not provided | 2015-01-15 | no assertion criteria provided | clinical testing | |
Service de Génétique Moléculaire, |
RCV001261072 | SCV001438474 | likely benign | Noonan syndrome | no assertion criteria provided | clinical testing | ||
Prevention |
RCV003944869 | SCV004760752 | likely benign | SOS1-related disorder | 2019-11-20 | no assertion criteria provided | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |