Submissions for variant NM_138694.4(PKHD1):c.6854G>A (p.Gly2285Glu)

gnomAD frequency: 0.00145  dbSNP: rs142526715

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224543	SCV000230603	uncertain significance	not provided	2018-05-30	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224543	SCV000280843	uncertain significance	not provided	2015-02-11	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000765886	SCV000897293	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000765886	SCV001000779	likely benign	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765886	SCV001327412	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000224543	SCV001983334	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24109560, 29642553, 21228398, 15805161, 16523049)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282003	SCV002571035	uncertain significance	not specified	2022-07-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6854G>A (p.Gly2285Glu) results in a non-conservative amino acid change located in the right handed beta helix domain (IPR039448) of 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 0.0013 in 250680 control chromosomes (gnomAD and Sharp_2005). This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0013 vs 0.0071), allowing no conclusion about variant significance. c.6854G>A has been reported in the literature in the compound heterozygous state in an individual affected with a milder, predominant biliary phenotype of polycystic kidney disease (Adeva_2006). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS n=5, likely benign n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224543	SCV004227249	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV003917663	SCV004733678	likely benign	PKHD1-related condition	2023-09-15	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.	RCV000765886	SCV001455258	uncertain significance	Autosomal recessive polycystic kidney disease	2019-12-19	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224543	SCV001744038	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844816	SCV001877013	likely benign	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224543	SCV001932579	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224543	SCV001969297	likely benign	not provided		no assertion criteria provided	clinical testing