ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.7916C>A (p.Ser2639Ter)

gnomAD frequency: 0.00003  dbSNP: rs181208607
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169564 SCV000221060 likely pathogenic Autosomal recessive polycystic kidney disease 2015-01-22 criteria provided, single submitter literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415427 SCV000492998 pathogenic Polycystic kidney disease 2013-12-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169564 SCV001163031 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001091108 SCV001246964 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169564 SCV001437301 pathogenic Autosomal recessive polycystic kidney disease 2020-09-17 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.7916C>A (p.Ser2639X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251146 control chromosomes (gnomAD). c.7916C>A has been reported in compound heterozygous and homozygous state in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Denamur_2010, Tavira_2015, Melchionda_2016, Szabo_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001374661 SCV001571429 pathogenic Polycystic kidney disease 4 2021-04-19 criteria provided, single submitter clinical testing
Invitae RCV000169564 SCV001582495 pathogenic Autosomal recessive polycystic kidney disease 2023-11-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser2639*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with polycystic kidney disease (PMID: 19940839, 27225849). ClinVar contains an entry for this variant (Variation ID: 189143). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814084 SCV001755195 pathogenic Abnormality of the genitourinary system 2021-07-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001374661 SCV002809895 pathogenic Polycystic kidney disease 4 2021-12-18 criteria provided, single submitter clinical testing
3billion RCV001374661 SCV004013505 pathogenic Polycystic kidney disease 4 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189143 / PMID: 19940839). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV001091108 SCV004014404 pathogenic not provided 2023-01-12 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19940839, 34249099, 27225849, 29956005)
Baylor Genetics RCV001374661 SCV004202226 pathogenic Polycystic kidney disease 4 2023-10-20 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169564 SCV002078005 pathogenic Autosomal recessive polycystic kidney disease 2017-08-31 no assertion criteria provided clinical testing

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