Submissions for variant NM_138694.4(PKHD1):c.8345G>C (p.Gly2782Ala)

gnomAD frequency: 0.00223  dbSNP: rs147222255

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082581	SCV000114623	likely benign	not specified	2015-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000473573	SCV000557652	likely benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000082581	SCV000592904	uncertain significance	not specified	2016-09-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000659055	SCV000780862	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000473573	SCV000799007	uncertain significance	Autosomal recessive polycystic kidney disease	2018-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082581	SCV000918005	likely benign	not specified	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8345G>C (p.Gly2782Ala) results in a non-conservative amino acid change located in the second G8 domain (IPR019316) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251184 control chromosomes, including 3 homozygotes (gnomAD, exomes dataset). The variant was predominantly found within the Non-Finnish European subpopulation at a frequency of 0.005 that is somewhat lower than the maximum expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.0071). c.8345G>C has been reported in the literature in an individual affected with Caroli Disease (example: Giacobbe_2022). The variant has also been reported in in the literature, where it was identified in 2/200 healthy control chromosomes (Sharp 2005, Bergmann 2005), and was listed as a polymorphism (benign) based on the criteria proposed by the authors. 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. Twelve other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant with conflicting assessments: likely pathogenic (n=1), VUS (n=6), benign/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000473573	SCV001325038	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II	RCV001507100	SCV001712071	uncertain significance	Caroli disease	2021-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000659055	SCV001819713	likely benign	not provided	2020-11-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32359821, 15698423, 15805161)
Mayo Clinic Laboratories, Mayo Clinic	RCV000659055	SCV002542180	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	PM2
PreventionGenetics, part of Exact Sciences	RCV003935071	SCV004756217	likely benign	PKHD1-related disorder	2020-10-27	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).
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000473573	SCV000680338	likely pathogenic	Autosomal recessive polycystic kidney disease	2017-12-07	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000659055	SCV001741754	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844807	SCV001876967	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000659055	SCV001927976	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000082581	SCV001969842	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000659055	SCV002036519	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000473573	SCV002077982	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing