ClinVar Genomic variation as it relates to human health

ACMG codes: PM2; PM3; PP3; PP5

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1971 of the PKHD1 protein (p.Gly1971Asp). This variant is present in population databases (rs180675584, gnomAD 0.009%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 12874454, 19940839). ClinVar contains an entry for this variant (Variation ID: 377269). 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 with a positive predictive value of 95%. 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 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 glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.01 (17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated G8 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenc by mulitple clinical laboratories in ClinVar, and has been observed as homozygous or compound heterozygous in several individuals with ARPKD (PMIDs: 22034641, 19021639, 15805161). (SP) 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: 31589614, 25263802, 14741187, 22034641, 12874454, 15805161, 19940839)

This individual is heterozygous for the c.5912G>A variant in the PKHD1 gene. This variant has been previously reported in patients with autosomal recessive polycystic kidney disease either in the homozygous form or compound heterozygous with a second pathogenic PKHD1 variant (Sharp et al J Med Genet 2005; 42:336-349; Bergmann et al 2011 J Am Soc Nephrol 22: 2047-2056). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.004% (12/ 276, 768 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines.

The PKHD1 c.5912G>A variant is predicted to result in the amino acid substitution p.Gly1971Asp. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2011. PubMed ID: 22034641; Furu et al. 2003. PubMed ID: 12874454; Sharp et al. 2005. PubMed ID: 15805161). This variant is reported in 0.009% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.