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

gnomAD frequency: 0.00008  dbSNP: rs369925690

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467466	SCV000545850	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Gharavi Laboratory, Columbia University	RCV000681918	SCV000809401	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Illumina Laboratory Services, 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.
Blueprint Genetics	RCV000681918	SCV000927626	pathogenic	not provided	2018-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000467466	SCV001137152	pathogenic	Autosomal recessive polycystic kidney disease	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000467466	SCV001163079	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000467466	SCV001194128	pathogenic	Autosomal recessive polycystic kidney disease	2019-12-26	criteria provided, single submitter	clinical testing	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.
Molecular Biology Laboratory, Fundació Puigvert	RCV000467466	SCV001425233	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000467466	SCV001427119	pathogenic	Autosomal recessive polycystic kidney disease	2018-05-21	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262841	SCV001440863	pathogenic	Polycystic kidney disease 4	2019-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001262841	SCV002024646	likely pathogenic	Polycystic kidney disease 4	2021-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000681918	SCV002028129	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	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)
Fulgent Genetics, Fulgent Genetics	RCV001262841	SCV002811605	pathogenic	Polycystic kidney disease 4	2022-03-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000681918	SCV002821378	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	PKHD1: PM3:Very Strong, PM2, PP4, BP4
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001262841	SCV003807093	pathogenic	Polycystic kidney disease 4	2022-04-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderated, PM2 moderated, PM3 very strong
PreventionGenetics, part of Exact Sciences	RCV003401465	SCV004104111	pathogenic	PKHD1-related condition	2023-10-12	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001262841	SCV004202227	pathogenic	Polycystic kidney disease 4	2023-10-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003985354	SCV004801713	pathogenic	See cases	2024-02-04	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PS4,PP4
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.
Natera, Inc.	RCV000467466	SCV002083397	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing