ClinVar Miner

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

gnomAD frequency: 0.00223  dbSNP: rs147222255
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Total submissions: 18
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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

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