Submissions for variant NM_138694.4(PKHD1):c.5585C>T (p.Ser1862Leu)

gnomAD frequency: 0.00022  dbSNP: rs147933501

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674056	SCV000799329	uncertain significance	Autosomal recessive polycystic kidney disease	2018-04-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730270	SCV000857996	uncertain significance	not provided	2017-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584545	SCV001821330	uncertain significance	not specified	2021-08-20	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5585C>T (p.Ser1862Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251294 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00025 vs 0.0071), allowing no conclusion about variant significance. c.5585C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Bergmann_2005, Gunay-Aygun_2010, Tong_2016). In addition, Zingg-Schenk et al (2012) reports the variant in compound heterozygosity with a pathogenic variant (p.Arg496X), in an individual that was asymptomatic at their most recent follow-up at the age of 13 years. These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002485562	SCV002788249	uncertain significance	Polycystic kidney disease 4	2022-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV000674056	SCV003523354	uncertain significance	Autosomal recessive polycystic kidney disease	2018-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 1862 of the PKHD1 protein (p.Ser1862Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs147933501, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with autosomal-recessive polycystic kidney disease(PMID: 15698423,  20415584). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Baylor Genetics	RCV002485562	SCV004202241	uncertain significance	Polycystic kidney disease 4	2023-10-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000674056	SCV002078076	uncertain significance	Autosomal recessive polycystic kidney disease	2019-06-10	no assertion criteria provided	clinical testing