Submissions for variant NM_138694.4(PKHD1):c.5125C>T (p.Leu1709Phe)

gnomAD frequency: 0.00371  dbSNP: rs45517932

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253664	SCV000315808	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000987715	SCV000629923	likely benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000253664	SCV000700702	likely benign	not specified	2016-10-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000558453	SCV000729458	likely benign	not provided	2020-06-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24162162, 30809968, 19940839, 20413436, 16133180, 15805161, 15108277, 12874454, 12846734)
Mendelics	RCV000987715	SCV001137143	likely benign	Autosomal recessive polycystic kidney disease	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000558453	SCV001154773	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PKHD1: BS2
Illumina Laboratory Services, Illumina	RCV000987715	SCV001327544	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253664	SCV002500409	likely benign	not specified	2022-03-15	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5125C>T (p.Leu1709Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251342 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0028 vs 0.0071), allowing no conclusion about variant significance. However, this variant was observed in high allele frequency (as high as 1.5%) in healthy controls in multiple publications and classified as polymorphism (Rossetti_2003, Bergmann_2014, Sharp_2005, Losekoot_2005). c.5125C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Gunay-Aygun_2010, Denamur_2010, Bullich_2018). 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. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four have classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000558453	SCV002542181	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	BS1
Natera, Inc.	RCV000987715	SCV002078091	likely benign	Autosomal recessive polycystic kidney disease	2017-05-08	no assertion criteria provided	clinical testing