Submissions for variant NM_138694.4(PKHD1):c.7675G>C (p.Val2559Leu)

gnomAD frequency: 0.00070  dbSNP: rs150046042

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178676	SCV000230801	uncertain significance	not provided	2018-03-15	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000178676	SCV000927493	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
Invitae	RCV000806672	SCV000946685	likely benign	Autosomal recessive polycystic kidney disease	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000806672	SCV001320060	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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	RCV001358740	SCV001554588	uncertain significance	not specified	2024-01-26	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7675G>C (p.Val2559Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 1613106 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0012 vs 0.0071), allowing no conclusion about variant significance. c.7675G>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease without strong evidence for causality (e.g. Sharp_2005, Tavira_2015). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 15805161, 25701400). ClinVar contains an entry for this variant (Variation ID: 197602). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003352795	SCV004054814	uncertain significance	Inborn genetic diseases	2023-08-02	criteria provided, single submitter	clinical testing	The c.7675G>C (p.V2559L) alteration is located in exon 48 (coding exon 47) of the PKHD1 gene. This alteration results from a G to C substitution at nucleotide position 7675, causing the valine (V) at amino acid position 2559 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003977466	SCV004795668	likely benign	PKHD1-related condition	2024-01-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000806672	SCV001455249	uncertain significance	Autosomal recessive polycystic kidney disease	2018-03-26	no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844817	SCV001877014	likely benign	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000178676	SCV001930057	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000178676	SCV001964007	likely benign	not provided		no assertion criteria provided	clinical testing