Submissions for variant NM_138694.4(PKHD1):c.6992T>A (p.Ile2331Lys)

gnomAD frequency: 0.00044  dbSNP: rs200179145

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169149	SCV000220374	likely pathogenic	Autosomal recessive polycystic kidney disease	2014-06-06	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000494184	SCV000331822	pathogenic	not provided	2018-07-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169149	SCV000464070	pathogenic	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	The PKHD1 c.6992T>A (p.Ile2331Lys) missense variant has been reported in four studies in which it is found in a total of 11 patients with autosomal recessive polycystic kidney disease, all in a compound heterozygous state, at least three of whom carried a frameshift variant on the second allele (Ward et al. 2002; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). Segregation with disease has been shown in at least two studies (Ward et al. 2002; Bergmann et al. 2005). The p.Ile2331Lys variant was absent from 500 controls and is reported at a frequency of 0.00287 in the European (Finnish) population in the Exome Aggregation Consortium. 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.
Invitae	RCV000169149	SCV000545847	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2331 of the PKHD1 protein (p.Ile2331Lys). This variant is present in population databases (rs200179145, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 11919560, 12506140, 15698423, 15805161, 19914852, 26673778). 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: 188813). 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.
GeneDx	RCV000494184	SCV000582473	pathogenic	not provided	2021-06-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12846734, 15805161, 12874454, 29956005, 14741187, 20413436, 16523049, 19914852, 15698423, 11919560, 15108277, 12506140, 15706593, 26673778, 29935118, 31980526, 27535533, 31589614)
Blueprint Genetics	RCV000494184	SCV000927562	pathogenic	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169149	SCV001163034	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169149	SCV001338101	pathogenic	Autosomal recessive polycystic kidney disease	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6992T>A (p.Ile2331Lys) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251478 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.00046 vs 0.0071), allowing no conclusion about variant significance. c.6992T>A has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney and Hepatic Disease (Ward_2002, Bergmann_2003, Bergmann_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Biology Laboratory, Fundació Puigvert	RCV000169149	SCV001425234	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001542752	SCV001427169	pathogenic	Polycystic kidney disease 4	2022-06-24	criteria provided, single submitter	clinical testing	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. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant intrafamilial variation of severity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (134 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated right handed beta helix (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and reported in compound heterozygous individuals with milder renal disease and autosomal recessive polycystic kidney disease (ClinVar, PMID: 33532864, PMID: 15698423). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in four affected pairs of siblings (PMID: 15698423). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomics England Pilot Project, Genomics England	RCV001542752	SCV001760184	likely pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001542752	SCV001976874	likely pathogenic	Polycystic kidney disease 4	2021-10-06	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001542752	SCV002499150	likely pathogenic	Polycystic kidney disease 4	2022-03-30	criteria provided, single submitter	clinical testing	PM3_Strong, PM1
Fulgent Genetics, Fulgent Genetics	RCV001542752	SCV002784900	pathogenic	Polycystic kidney disease 4	2022-04-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001542752	SCV004032310	pathogenic	Polycystic kidney disease 4	2023-08-21	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM1,PM2_SUP
Baylor Genetics	RCV001542752	SCV004204031	pathogenic	Polycystic kidney disease 4	2023-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000494184	SCV004700468	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PKHD1: PM3:Very Strong, PM1, PM2, BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291886	SCV000592899	likely pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ile2331Lys variant was identified in 15 of 836 proband chromosomes (frequency: 0.018) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Adeva 2006, Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Sharp 2005). The variant was also identified in dbSNP (ID: rs200179145) as “With likely pathogenic allele”, Clinvitae database (likely pathogenic by ClinVar), the ClinVar database (likely pathogenic by Counsyl), RWTH AAachen University ARPKD database (pathogenic) and PKHD1-LOVD. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 40 of 121394 chromosomes (freq. 0.0003) in the following populations: European in 21 of 66734 chromosomes (freq. 0.0003), Finish in 19 of 6614 chromosomes (freq. 0.003) and not identified in African, East Asian, Latino, South Asian or Other population. The p.Ile2331 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In the case study by Adeva (2006) the variant was identified with a truncating mutation in an infant with respiratory distress and hyperechogenic liver and kidneys with intrahepatic bile duct dilatation, the variant was classified as definitely pathogenic. Two ARPKD studies classified the variant as pathogenic (Sharp 2005) and probably pathogenic (Gunay-Aygun 2010) by in silico and segregation analysis. In addition, Bergmann (2005) and Furu (2004) suggest the variant in combination with truncating mutation has a rather moderate effect and associated with minor renal disease. 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.
Natera, Inc.	RCV000169149	SCV002078033	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing