Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000612075 | SCV000712601 | likely pathogenic | Noonan syndrome | 2016-11-17 | criteria provided, single submitter | clinical testing | The p.Glu891Lys variant in SOS1 has been identified by our laboratory as a de no vo variant in one individual with clinical features of Noonan syndrome. This var iant was absent from large population studies. Computational prediction tools an d conservation analysis do not provide strong support for or against an impact t o the protein. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Glu891Lys variant is likely pathogenic. |
Victorian Clinical Genetics Services, |
RCV002470931 | SCV002767052 | uncertain significance | Noonan syndrome 4 | 2020-05-26 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3A-VUS. Following criteria are met: 0101 - Gain of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 16). It is also a non-canonical splice region variant without proven consequence on splicing (no functional evidence available). 0301 - Variant is absent from gnomAD. 0502 - Missense variant with conflicting in silico predictions and high conservation. Abnormal splicing is not predicted by in silico tools. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (RasGEF domain; PDB, NCBI). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. It has been previously reported likely pathogenic in a patient with Noonan syndrome (ClinVar). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1205 - Variant is maternally inherited. |
Labcorp Genetics |
RCV002529338 | SCV003457381 | uncertain significance | RASopathy | 2022-05-25 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 891 of the SOS1 protein (p.Glu891Lys). ClinVar contains an entry for this variant (Variation ID: 505408). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. |
Center for Genomic Medicine, |
RCV002470931 | SCV004805528 | likely pathogenic | Noonan syndrome 4 | 2024-03-25 | criteria provided, single submitter | research |