ClinVar

Description

The PKD1 p.Thr2422Lys variant was identified in 2 of 214 proband chromosomes (frequency: 0.009) from individuals or families with polycystic kidney disease and classified probably pathogenic (Garcia-Gonzalez 2007, Tan 2009). The variant was also identified in ADPKD Mutation Database and classified as highly likely pathogenic. The variant was not identified in dbSNP, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium database, Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The p.Thr2422 residue is conserved across mammals and other organisms, and four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.