ClinVar Genomic variation as it relates to human health

Variant summary: The PKHD1 c.664A>G (p.Ile222Val) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/120972 control chromosomes at a frequency of 0.0000992, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in numerous ARPKD patients. Taken together, this variant is classified as pathogenic.

The heterozygous p.Ile222Val variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Ile222Val variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010).

The PKHD1 c.664A>G (p.Ile222Val) missense variant has been reported in six studies and in a total of 18 individuals with autosomal recessive polycystic kidney disease, all in a compound heterozygous state (Ward et al. 2002; Onuchic et al. 2002; Rossetti et al. 2003; Bergmann et al. 2003; Gunay-Aygun et al. 2010; Brinkert et al. 2013). Segregation with disease has been shown in seven families (Ward et al. 2002; Onuchic et al. 2002; Rossetti et al. 2003; Bergmann et al. 2003; Gunay-Aygun et al. 2010). The p.Ile222Val variant was absent from 460 controls and is reported at a frequency of 0.000494 in the Ashkenazi Jewish population in the Genome Aggregation Database. Based on the collective evidence, the p.Ile2331Lys variant is classified as pathogenic for autosomal recessive polycystic disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

NM_138694.3(PKHD1):c.664A>G(I222V) is classified as pathogenic in the context of PKHD1-related, autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 19914852, 15698423, 12846734, 19940839, 11919560 and 12925574. Classification of NM_138694.3(PKHD1):c.664A>G(I222V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

A heterozygous missense variant, NM_138694.3(PKHD1):c.664A>G, has been identified in exon 9 of 67 of the PKHD1 gene. The variant is predicted to result in a minor amino acid change from isoleucine to valine at position 222 of the protein (NP_619639.3(PKHD1):p.(Ile222Val). The isoleucine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within any domains. In-silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the database at a frequency of 0.01% (28/276558 heterozygotes and 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with polycystic kidney disease (Onuchic, L. et al. 2002, Rosetti S. et al. 2003, Obeidova L. et al. 2015, Gunay-Aygun M. et al. 2010). It has also been shown to segregate with the disease in at least one family (Ward C. et al. 2002). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which could be consistent with polycystic kidney disease.

ACMG classification criteria: PS4 moderated, PM2 moderated, PM3 very strong

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11898128, 16133180, 30586318, 11919560, 15698423, 12506140, 26695994, 12846734, 20413436, 15805161, 25701400, 27225849, 30650191, 32574212, 34249099, 31589614, 32939031)

The PKHD1 c.664A>G variant is predicted to result in the amino acid substitution p.Ile222Val. This variant has been repeatedly reported to be causative for autosomal recessive polycystic kidney disease (ARPKD) (Ward et al. 2002. PubMed ID: 11919560; Shuster et al. 2019. PubMed ID: 30650191; Obeidova et al. 2020. PubMed ID: 32574212; Jayasinghe et al. 2020. PubMed ID: 32939031). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51935807-T-C). This variant is interpreted as pathogenic.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 222 of the PKHD1 protein (p.Ile222Val). This variant is present in population databases (rs369925690, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11919560, 12506140, 12846734, 15698423, 19914852, 26695994). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406891). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.

ACMG categories: PS3,PS4,PP4

PKHD1: PM3:Very Strong, PM2, PP4, BP4

Variant interpretted as pathogenic and reported on 03/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.