ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1486C>T (p.Arg496Ter) (rs137852949)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723837 SCV000331544 pathogenic not provided 2015-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004330 SCV000699850 pathogenic Autosomal recessive polycystic kidney disease 2016-08-25 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.1486C>T (p.Arg496X) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 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 (e.g.c.9319C>T/p.Arg3107X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 69/121402 control chromosomes at a frequency of 0.0005684, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Variant was primarily detected in Finnish European population in both controls and cases, and it was reported as a founder mutation for Finnish population. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Blueprint Genetics RCV000723837 SCV000927414 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000004330 SCV001163065 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
GeneDx RCV000723837 SCV001167698 pathogenic not provided 2019-10-03 criteria provided, single submitter clinical testing Observed in homozygous state and with a pathogenic variant on the opposite allele (in trans) in multiple unrelated patients in published literature and not observed in homozygous state in controls; described as a Finnish founder mutation in this study (Bergmann et al., 2003); Observed multiple times with a pathogenic variant in published literature and in a patient referred for genetic testing at GeneDx, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Gunay-Aygun et al., 2010); Reported heterozygous in a patient with polycystic liver disease (Besse et al., 2017); 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; Observed in 0.0704% (199/282614 alleles) in large population cohorts (Lek et al., 2016)
Myriad Women's Health, Inc. RCV000004330 SCV001193870 pathogenic Autosomal recessive polycystic kidney disease 2019-11-11 criteria provided, single submitter clinical testing NM_138694.3(PKHD1):c.1486C>T(R496*) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 12506140 and 15698423. Classification of NM_138694.3(PKHD1):c.1486C>T(R496*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000723837 SCV001246968 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
OMIM RCV000004330 SCV000024501 pathogenic Autosomal recessive polycystic kidney disease 2003-01-01 no assertion criteria provided literature only
Yale Center for Mendelian Genomics,Yale University RCV000845135 SCV000987071 likely pathogenic Polycystic liver disease 2017-04-04 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000004330 SCV001142360 pathogenic Autosomal recessive polycystic kidney disease 2020-01-06 no assertion criteria provided curation NM_138694.3:c.1486C>T in the PKHD1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. The PKHD1 c.1486C>T (p.Arg496*) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant has been reported in patients with autosomal recessive polycystic kidney disease, including six homozygotes, five compound heterozygotes (with V3471G and D2761Y) (PMID: 12506140; 15698423). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3_Strong, PP4.

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