Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000466683 | SCV000551598 | uncertain significance | Perlman syndrome | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 576 of the DIS3L2 protein (p.Arg576His). This variant is present in population databases (rs200386096, gnomAD 0.03%). This missense change has been observed in individual(s) with sporadic Wilm's tumor (PMID: 22306653). ClinVar contains an entry for this variant (Variation ID: 410737). 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. |
| Fulgent Genetics, |
RCV000466683 | SCV000895427 | uncertain significance | Perlman syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000466683 | SCV002030087 | uncertain significance | Perlman syndrome | 2021-04-29 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Revvity Omics, |
RCV000466683 | SCV003834680 | uncertain significance | Perlman syndrome | 2022-03-30 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001356582 | SCV001551793 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The DIS3L2 p.R576H variant was identified in the literature as a heterozygous variant in a sporadic Wilms tumor and was not found in >200 control samples; when this variant was expressed in stably transfected HEK293 cells, it did not suppress anchorage-independent cell growth (Astuti_2012_PMID:22306653). The variant was identified in dbSNP (ID: rs200386096) and ClinVar (classified as uncertain significance by Fulgent Genetics and Invitae for Renal hamartomas nephroblastomatosis and fetal gigantism). The variant was identified in control databases in 36 of 265924 chromosomes at a frequency of 0.0001354 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 10 of 35026 chromosomes (freq: 0.000286), European (non-Finnish) in 19 of 117256 chromosomes (freq: 0.000162), Other in 1 of 6606 chromosomes (freq: 0.000151), South Asian in 4 of 30504 chromosomes (freq: 0.000131) and African in 2 of 22846 chromosomes (freq: 0.000088), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.R576 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. |