Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000687679 | SCV000815263 | uncertain significance | Perlman syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 522 of the DIS3L2 protein (p.Ser522Gly). This variant is present in population databases (rs199980393, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 567559). 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 DIS3L2 protein function with a negative predictive value of 80%. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001354878 | SCV001549595 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The DIS3L2 p.Ser522Gly variant was not identified in the literature but was identified in dbSNP (ID: rs199980393) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 5 of 266288 chromosomes at a frequency of 0.00001878 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the European (non-Finnish) population in 5 of 117552 chromosomes (freq: 0.000043), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Ser522 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |