ClinVar Genomic variation as it relates to human health

This variant is interpreted as Pathogenic for Polycystic kidney disease, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in gnomAD (PM2 downgraded to supporting); For recessive disorders, detected in trans with a pathogenic variant (PM3 upgraded to very strong; PMID: 11898128, 12506140, 12874454, 15805161, 16133180, 25701400, 26695994); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3).

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: 32949114, 34853893, 34405919, 34645488, 30586318, 31130284, 27843768, 16133180, 11898128, 25701400, 19914852, 27401137, 27894351, 27151922, 28454995, 30202406, 31844813, 32799815, 31980526, 32571524, 32574212, 32398770, 34426522, 35812281, 36177613, 37644014, 35325889, 38178268, 35715958, 37078890, 37464296, 36938085)

Variant summary: The PKHD1 c.4870C>T (p.Arg1624Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not functional for this variant). This variant was found in 22/121594 control chromosomes at a frequency of 0.0001809, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in at least 6 ARPKD patients in heterozygous or homozygous state (Obeidova_2015, Sharp_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Across a selection of the available literature, the PKHD1 c.4870C>T (p.Arg1624Trp) missense variant has been identified in a total of nine individuals with autosomal recessive polycystic kidney disease (ARPKD), including two siblings from a consanguineous union who presented a milder, later-onset phenotype and carried the variant in a homozygous state, six individuals who carried the variant in a compound heterozygous state and presented a range of phenotypes, and one individual with a milder, later-onset phenotype who was heterozygous for the variant (Onuchic et al. 2002; Losekoot et al. 2005; Gunay-Aygun et al. 2010). The p.Arg1624Trp variant was also identified in a heterozygous state in a total of four unaffected parents of individuals with ARPKD and was absent from 60 controls (Onuchic et al. 2002). The variant is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1624Trp variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

NM_138694.3(PKHD1):c.4870C>T(R1624W) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 27225849, 16133180, 19914852 and 11898128. Classification of NM_138694.3(PKHD1):c.4870C>T(R1624W) 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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1624 of the PKHD1 protein (p.Arg1624Trp). This variant is present in population databases (rs200391019, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16133180, 19914852, 26695994, 27225849; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188369). 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 not expected to disrupt PKHD1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

A Heterozygous Missense variant c.4870C>T in Exon 32 of the PKHD1 gene that results in the amino acid substitution p.Arg1624Trp was identified. The observed variant has a maximum allele frequency of 0.00015/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as [Pathogenic/Likely Pathogenic/Uncertain Significance] Conflicting Interpretations [Variation ID: 188369]. The observed variation has been observed in individual(s) with autosomal recessive polycystic kidney disease (Gunay-Aygun M, et.al., 2010). For these reasons, this variant has been classified as Likely Pathogenic.

The missense variant c.4870C>T (p.Arg1624Trp) in PKHD1 gene has been identified in a total of nine individuals with autosomal recessive polycystic kidney disease (ARPKD), including two siblings from a consanguineous union who presented a milder, later-onset phenotype and carried the variant in a homozygous state, six individuals who carried the variant in a compound heterozygous state and presented a range of phenotypes, and one individual with a milder, later-onset phenotype who was heterozygous for the variant (Gunay-Aygun et al. 2010; Losekoot et al. 2005; Onuchic et al. 2002). The p.Arg1624Trp variant was also identified in a heterozygous state in a total of four unaffected parents of individuals with ARPKD and was absent from 60 controls (Onuchic et al. 2002). The observed variant has allele frequency of 0.02% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg1624Trp in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1624 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

The PKHD1 p.Arg1624Trp variant was identified in 28 of 696 proband chromosomes (frequency: 0.04) from individuals or families with ARPKD and was not identified in 200 control chromosomes from healthy individuals (Edrees 2016,Gunay-Aygun 2010, Losekoot 2005, Melchionda 2016, Obeidova 2015, Sharp 2005). The variant was also identified in dbSNP (ID: rs200391019) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, GeneDx and four clinical laboratories; as likely pathogenic by Counsyl; as uncertain significance by SIB Swiss Institute of Bioinformatics), LOVD 3.0 (3x), and in RWTH AAachen University ARPKD database (as pathogenic or probably pathogenic), databases. The variant was not identified in COGR database. The variant was identified in control databases in 40 of 277158 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 28 of 126656 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10144 chromosomes (freq: 0.0001), and South Asian in 3 of 30780 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, or Finnish populations. The p.Arg1624 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

The PKHD1 c.4870C>T variant is predicted to result in the amino acid substitution p.Arg1624Trp. This variant has been repeatedly reported in patients with later-onset autosomal recessive polycystic kidney disease (ARPKD), either in the homozygous state or in trans with another pathogenic PKHD1 variant (Onuchic et al. 2002. PubMed ID: 11898128; Sharp et al. 2005. PubMed ID: 15805161; Losekoot et al. 2005. PubMed ID: 16133180). This variant is reported in 0.022% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

This individual is heterozygous for the c.4870C>T variant in the PKHD1 gene. This variant has been reported in the literature in several different families with autosomal recessive polycystic kidney disease (ARPKD) as both homozygous and compound heterozygous, usually associated with a late onset or milder phenotype (e.g. Onuchic et al 2002 Am J Hum Genet 70: 1305-1317; Sharp et al 2005 J Met Genet 42: 336-349; ). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.014% (40 out of 277,158 alleles). This variant is considered to be pathogenic according to the ACMG guidelines.