Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000427750 | SCV000534669 | uncertain significance | not provided | 2018-03-12 | criteria provided, single submitter | clinical testing | The G338S variant in the GCNT2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G338S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G338S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.1012G>A (aka G338S) might destroy the natural splice donor site in intron 2, and may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.1012G>A in this individual is unknown. We interpret G338S as a variant of uncertain significance. |
| Labcorp Genetics |
RCV002525476 | SCV003264236 | likely pathogenic | Cataract 13 with adult I phenotype | 2022-06-09 | criteria provided, single submitter | clinical testing | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 391563). This missense change has been observed in individual(s) with congenital cataracts (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs568547927, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 338 of the GCNT2 protein (p.Gly338Ser). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |