Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002571905 | SCV002930249 | uncertain significance | not provided | 2023-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 339 of the C1S protein (p.Ser339Leu). This variant is present in population databases (rs781913781, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with C1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 1896277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt C1S protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Neuberg Centre For Genomic Medicine, |
RCV004763430 | SCV005373518 | uncertain significance | Ehlers-Danlos syndrome, periodontal type 2 | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense c.1016C>T(p.Ser339Leu) variant in C1S gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.002% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance. Computational evidence (Polyphen - possibly damaging, SIFT - Tolerated and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 339 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). |