ClinVar

Description

The PKHD1 p.Pro2089Leu variant was not identified in the literature nor was it identified in ClinVar, LOVD 3.0 or the RWTH AAachen University ARPKD database. The variant was identified in dbSNP (ID: rs376477480) and in control databases in 2 of 251138 chromosomes at a frequency of 0.000007964 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 1 of 34534 chromosomes (freq: 0.000029) and European (non-Finnish) in 1 of 113510 chromosomes (freq: 0.000009), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Pro2089 residue is not conserved in mammals and four out of five 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.