Submissions for variant NM_138694.4(PKHD1):c.5498C>T (p.Ser1833Leu)

gnomAD frequency: 0.00009  dbSNP: rs201105958

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723529	SCV000700545	uncertain significance	not provided	2016-12-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000592600	SCV000794968	uncertain significance	Autosomal recessive polycystic kidney disease	2017-10-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000592600	SCV000897295	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000592600	SCV000915171	uncertain significance	Autosomal recessive polycystic kidney disease	2018-03-23	criteria provided, single submitter	clinical testing	The PKHD1 c.5498C>T (p.Ser1833Leu) missense variant has been reported in three studies and is found in three individuals with autosomal recessive polycystic kidney disease, two in a compound heterozygous state and one in whom zygosity was not specified, but who also carried two other variants (Rossetti et al. 2003; Gunay-Aygun et al. 2010; Tong et al. 2016). Probands exhibited phenotypes including medullary sponge kidney, Caroli's disease, and congenital hepatic fibrosis (Rossetti et al. 2003; Gunay-Aygun et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000293 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Ser1833Leu variant is 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.
Baylor Genetics	RCV000592600	SCV001163042	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV000592600	SCV001434251	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000592600	SCV003204108	likely pathogenic	Autosomal recessive polycystic kidney disease	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1833 of the PKHD1 protein (p.Ser1833Leu). This variant is present in population databases (rs201105958, gnomAD 0.03%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 12846734, 19914852, 27752906, 33282801, 33940108, 35812281). ClinVar contains an entry for this variant (Variation ID: 496898). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000592600	SCV003844295	pathogenic	Autosomal recessive polycystic kidney disease	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5498C>T (p.Ser1833Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251130 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00017 vs 0.0071), allowing no conclusion about variant significance. c.5498C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease, and segregated with disease within families (e.g. Burgmaier_2021). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likey pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000723529	SCV003936498	likely pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	Observed phase unknown with a second variant in a patient with congenital hepatic fibrosis, Caroli's disease, and medullary sponge kidney in published literature (PMID: 12846734); 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: 26489027, 30809968, 14741187, 34405919, 33282801, 19914852, 27752906, 33940108, 35812281, 38051388, 12846734)
Baylor Genetics	RCV003471950	SCV004202209	likely pathogenic	Polycystic kidney disease 4	2024-03-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723529	SCV001978355	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723529	SCV001979460	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748832	SCV005360071	likely pathogenic	PKHD1-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The PKHD1 c.5498C>T variant is predicted to result in the amino acid substitution p.Ser1833Leu. This variant was reported with a second missense variant in an adult (38 years old) patient with cholangitis, medullary sponge kidney and cyst in a genetic study of patients with autosomal recessive polycystic kidney disease (ARPKD) (Rossetti et al. 2003. PubMed ID: 12846734). In addition, this variant was reported with a pathogenic (splice or exon-level deletion) variant in two unrelated families affected by ARPKD (Table S1 of Ajiri et al. 2022. PubMed ID: 35812281). Moreover, we have previously observed this variant together with a frameshift variant in two unrelated children tested for polycystic kidney disease at PreventionGenetics (internal data). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. Of note, this variant has been suggested to be incompletely penetrant (Mikó et al. 2021. PubMed ID: 34405919).