ClinVar Genomic variation as it relates to human health

The PKHD1 c.9719G>T variant is predicted to result in the amino acid substitution p.Arg3240Leu. This variant was reported along with a second PKHD1 variant in a prenatal case of autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). Internally, we have observed this variant in the compound heterozygous state with a second PKHD1 variant in two families with individuals affected with ARPKD. An alternate substitution impacting the same amino acid (p.Arg3240Gln) has also been reported in patients with ARPKD (e.g., Bergmann et al. 2005. PubMed ID: 15698423; https://www.ncbi.nlm.nih.gov/clinvar/variation/572902). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51612695-C-A). Taken together, this variant is interpreted as likely pathogenic.

Variant summary: The c.9719G>T (pArg3240Leu) in PKHD1 gene is a missense variant involves a conserved nucleotide located outside of any known functional domain or repeat. The 4/4 in silico tools used predict damaging outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.9719G>T was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245990 chrs tested). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.007, suggesting that it is not a common polymorphism. The variant has been reported in compound heterozygosity in 1 fetal sample with confirmed dx of ARPKD and is cited as VUS/Likely Pathogenic by reputable databases/clinical laboratories. In addition, other alterations of Arg3240 codon have been reported in association with ARPKD. Taken together, the variant was classified as VUS-Possibly Pathogenic, until new information becomes available.

ClinVar contains an entry for this variant (Variation ID: 167478). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3240 of the PKHD1 protein (p.Arg3240Leu). This variant is present in population databases (rs146649803, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15805161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 expected to disrupt PKHD1 protein function. This variant disrupts the p.Arg3240 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15698423, 19914852, 20413436, 24162162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease, however there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intra-familial variability has been reported (PMID: 20301501). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg3240Gln) has been classified as likely pathogenic or pathogenic by several clinical laboratories in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and as a VUS by clinical laboratories in ClinVar, and has also been observed in a fetus with ARPKD who also had another missense variant (PMID: 15805161). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9511976, 38300123, 38839463, 15805161, 15698423, 24162162)