ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.664A>G (p.Ile222Val) (rs369925690)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000681918 SCV000927626 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000467466 SCV000786707 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter research 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).
Counsyl RCV000467466 SCV000678113 pathogenic Autosomal recessive polycystic kidney disease 2017-05-30 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000467466 SCV000986736 not provided Autosomal recessive polycystic kidney disease no assertion provided phenotyping only 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.
Gharavi Laboratory,Columbia University RCV000681918 SCV000809401 pathogenic not provided 2018-09-16 no assertion criteria provided research
Illumina Clinical Services Laboratory,Illumina RCV000467466 SCV000915172 pathogenic Autosomal recessive polycystic kidney disease 2018-11-01 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000467466 SCV000699873 pathogenic Autosomal recessive polycystic kidney disease 2016-11-23 criteria provided, single submitter clinical testing 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.
Invitae RCV000467466 SCV000545850 pathogenic Autosomal recessive polycystic kidney disease 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 222 of the PKHD1 protein (p.Ile222Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs369925690, ExAC 0.02%). This variant segregates with disease and has been observed on the opposite chromosome (in trans) from a pathogenic variant in several families and individuals affected with autosomal recessive polycystic kidney disease (PMID: 26695994, 11919560, 12506140, 15698423, 12846734, 19914852). ClinVar contains an entry for this variant (Variation ID: 406891). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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