Submissions for variant NM_138694.4(PKHD1):c.7264T>G (p.Cys2422Gly)

dbSNP: rs201881567

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457585	SCV000545843	uncertain significance	Autosomal recessive polycystic kidney disease	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2422 of the PKHD1 protein (p.Cys2422Gly). This variant is present in population databases (rs201881567, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 12874454, 15698423, 20413436, 26489029, 33940108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406887). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000457585	SCV000799602	uncertain significance	Autosomal recessive polycystic kidney disease	2018-04-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729736	SCV000857423	uncertain significance	not provided	2017-10-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000457585	SCV000915170	uncertain significance	Autosomal recessive polycystic kidney disease	2018-08-21	criteria provided, single submitter	clinical testing	The PKHD1 c.7264T>G (p.Cys2422Gly) missense variant has been reported in two studies and found in a total of four individuals with autosomal recessive polycystic kidney disease, including three individuals from two families in a compound heterozygous state and one neonate in a heterozygous state in whom a second variant was not identified (Furu et al. 2003; Bergmann et al. 2005). In all the three compound heterozygous individuals, the p.Cys2422Gly variant was found in trans with an established pathogenic variant, p.Thr36Met. The p.Cys2422Gly variant was absent from a total of 360 controls and is reported at a frequency of 0.00378 in the European (Finnish) population of the Exome Aggregation Consortium. One homozygote is reported in the European (Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Cys2422Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000729736	SCV001989324	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	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: 14741187, 20413436, 34405919, 26489029, 27752906, 12874454, 33940108, 15698423)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457585	SCV002547681	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-06-01	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7264T>G (p.Cys2422Gly) results in a non-conservative amino acid change located in the Parallel beta-helix repeat (IPR006626) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251278 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0005 vs 0.0071), allowing no conclusion about variant significance. c.7264T>G has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney And Hepatic Disease and was found to segregate with disease in affected families (e.g. Furu_2003, Bergmann_2005, Braun_2016, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid residue has been classified pathogenic in ClinVar, this suggests that this residue may be functionally critical for normal protein function (CV ID 1494871). The following publications have been ascertained in the context of this evaluation (PMID: 15698423, 26489029, 33940108, 12874454). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV003334387	SCV004042806	likely pathogenic	Polycystic kidney disease 4	2023-01-31	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PM3, PM5, PP3_MOD
CeGaT Center for Human Genetics Tuebingen	RCV000729736	SCV004163597	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PKHD1: PM3:Strong, PM2, PM5
Baylor Genetics	RCV003334387	SCV004204032	likely pathogenic	Polycystic kidney disease 4	2024-03-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003334387	SCV004238586	likely pathogenic	Polycystic kidney disease 4	2022-09-15	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003334387	SCV005051934	likely pathogenic	Polycystic kidney disease 4	2024-02-01	criteria provided, single submitter	curation
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844833	SCV001876982	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003942478	SCV004762649	likely pathogenic	PKHD1-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The PKHD1 c.7264T>G variant is predicted to result in the amino acid substitution p.Cys2422Gly. In the compound heterozygous state with different pathogenic PKHD1 variants, this variant has been reported in unrelated individuals with autosomal recessive polycystic kidney disease (ARPKD) (Furu et al. 2003. PubMed ID: 12874454; Bergmann et al. 2005. PubMed ID: 15698423; Supplementary Table 2 at Braun et al. 2016. PubMed ID: 26489029). Of note, a different change affecting the same codon (c.7264T>C, p.Cys2422Arg) has also been reported in an ARPKD individual (Gunay-Aygun et al. 2010. PubMed ID: 19914852). In summary, the c.7264T>G (p.Cys2422Gly) variant is interpreted as likely pathogenic. Of note, this variant has been suggested to be incompletely penetrant (Mikó et al. 2021. PubMed ID: 34405919).