Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV002486484 | SCV002785337 | uncertain significance | Polycystic kidney disease 4 | 2021-08-19 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002547650 | SCV003461946 | uncertain significance | Autosomal recessive polycystic kidney disease | 2021-12-30 | 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 2694 of the PKHD1 protein (p.Ser2694Gly). This variant is present in population databases (rs775472136, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050069). 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 PKHD1 protein function. 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, |
RCV001356924 | SCV001552218 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The PKHD1 p.Ser2694Gly variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs775472136) and in control databases in 3 of 251188 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 1 of 10070 chromosomes (freq: 0.000099) and European (non-Finnish) in 2 of 113518 chromosomes (freq: 0.000018), while the variant was not observed in the African, Latino, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing. The p.Ser2694 residue is not conserved in mammals and four out of five computational analyses (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. 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. |