rs562488184

Description

The PKD1 p.Leu4026= variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with autosomal dominant polycystic kidney disease (Rossetti 2012). The variant was identified in dbSNP (rs562488184) as “NA” and ADPKD Mutation Database (observed 3x). The variant was not identified in the ClinVar, LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 66 of 278,404 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 51 of 30,578 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), African in 10 of 24,576 chromosomes (freq: 0.0004), Other in 1 of 7138 chromosomes (freq: 0.0001), and European in 4 of 125,806 chromosomes (freq: 0.00003); it was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The variant was observed in our laboratory in an individual with a co-occurring pathogenic PKD1 variant (p.Trp887*), decreasing the likelihood that this variant has clinical significance. The p.Leu4026= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.