ClinVar Genomic variation as it relates to human health

This frameshifting variant in exon 5 of 67 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with neonatal polycystic kidney disease (PMID: 12846734). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/251456) and thus is presumed to be rare. Based on the available evidence, the c.383del (p.Thr128IlefsTer25) variant is classified as Pathogenic.

Variant summary: PKHD1 c.383delC (p.Thr128IlefsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251456 control chromosomes (gnomAD). c.383delC has been reported in the literature in compound heterozygous individuals affected with Polycystic Kidney And Hepatic Disease that did not survice to adulthood (examples: Rossetti_2003, Bergmann_2005, Krall_2014, and Bullich_2018). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 594678). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12846734). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Thr128Ilefs*25) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839).

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 15108277, 15706593, 12846734)

The PKHD1 p.Thr128Ilefs*25 variant was identified in 3 of 450 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD (Bergmann 2005, Rosetti 2003). The variant was also identified in dbSNP (ID: rs868562051), LOVD 3.0, and in RWTH AAachen University ARPKD database (as pathogenic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.383del variant is predicted to cause a frameshift, which alters the protein amino acid sequence beginning at codon 128 and leads to a premature stop codon at position 152. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PKHD1 gene are an established mechanism of disease in ARPKD and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The PKHD1 c.383delC variant is predicted to result in a frameshift and premature protein termination (p.Thr128Ilefs*25). This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Rossetti et al. 2003. PubMed ID: 12846734). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.