ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.10219C>T (p.Gln3407Ter) (rs781368899)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000627228 SCV000231864 pathogenic not provided 2014-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000627228 SCV000748217 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The Q3407X variant in the PKHD1 gene has been reported previously in the homozyous state or in trans with a second PKHD1 variant in multiple patients with ARPKD (Bergmann et al., 2004; Losekoot et al., 2005; Fischer et al., 2009; Becker et al., 2010). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q3407X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q3407X as a pathogenic variant.
Invitae RCV000844922 SCV001204146 pathogenic Autosomal recessive polycystic kidney disease 2019-11-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln3407*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781368899, ExAC 0.005%). This variant has been observed in individuals affected with polycystic kidney disease (PMID: 15108281, 16133180). ClinVar contains an entry for this variant (Variation ID: 198314). Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000844922 SCV001362928 pathogenic Autosomal recessive polycystic kidney disease 2019-08-19 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.10219C>T (p.Gln3407X) 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 1.2e-05 in 250288 control chromosomes. c.10219C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2004, Losekoot_2005, Adeva_2006, Christiane Fischer_2009, Becker_2010). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics,Johns Hopkins University RCV000844922 SCV001425424 pathogenic Autosomal recessive polycystic kidney disease 2020-04-24 criteria provided, single submitter clinical testing This nonsense variant results in a premature stop codon in exon 61 likely leading to nonsense-mediated decay and lack of protein production. This variant has been reported in multiple patients with autosomal recessive polycystic kidney disease. PKHD1 c.10219C>T (rs781368899) is rare (<0.1%) in a large population dataset (gnomAD: 3/250288 total alleles; 0.001%; no homozygotes). Four submitters in ClinVar classify this variant as pathogenic or likely pathogenic. We consider this variant to be pathogenic.
GenomeConnect, ClinGen RCV000844922 SCV000986737 not provided Autosomal recessive polycystic kidney disease no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 03/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Yale Center for Mendelian Genomics,Yale University RCV000845132 SCV000987068 likely pathogenic Polycystic liver disease 2017-04-04 no assertion criteria provided literature only

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