ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs147933501
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Total submissions: 7
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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 2023-12-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp 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

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