ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.3761_3762delinsG (p.Ala1254fs) (rs398124484)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169008 SCV000220148 likely pathogenic Autosomal recessive polycystic kidney disease 2014-03-05 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790791 SCV000229573 pathogenic not provided 2014-04-03 criteria provided, single submitter clinical testing
Invitae RCV000169008 SCV000545848 pathogenic Autosomal recessive polycystic kidney disease 2018-12-26 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 1 nucleotide into exon 32 of the PKHD1 mRNA (c.3761_3762delinsG), causing a frameshift at codon 1254. This creates a premature translational stop signal (p.Ala1254Glyfs*49) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs746972457, ExAC 0.2%). This variant has been reported in the literature in several families and individuals affected with autosomal recessive polycystic kidney disease (PMID: 19914852, 26721323, 15805161, 11898128, 12874454, 12846734, 20413436). ClinVar contains an entry for this variant (Variation ID: 96398). 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 RCV000169008 SCV000699862 pathogenic Autosomal recessive polycystic kidney disease 2019-05-31 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.3761_3762delinsG (p.Ala1254GlyfsX49) 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 8e-06 in 251498 control chromosomes. c.3761_3762delinsG has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (homozygous and compound heterozygous individuals), and authors indicate the variant is a Ashkenazi Jewish founder mutation. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000169008 SCV000711731 pathogenic Autosomal recessive polycystic kidney disease 2018-12-06 criteria provided, single submitter clinical testing The p.Ala1254GlyfsX49 variant in PKHD1 has been reported in the homozygous or co mpound heterozygous state in at least 10 individuals with polycystic kidney dise ase and segregated with disease in 1 affected relative (Onuchic 2002, Furu 2003, Rossetti 2003, Sharp 2005, Quint 2016). It has also been identified in 0.7% (73 /10332) of Ashkenazi Jewish and 0.12% (43/35412) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 1254 and leads to a premature termination codon 49 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Loss of functi on of the PKHD1 gene is an established disease mechanism in autosomal recessive polycystic kidney disease. In summary, this variant meets criteria to be classif ied as pathogenic for autosomal recessive polycystic kidney disease. ACMG/AMP Cr iteria applied: PVS1, PM3_Very Strong; PP1.
Illumina Clinical Services Laboratory,Illumina RCV000169008 SCV000916156 pathogenic Autosomal recessive polycystic kidney disease 2018-10-22 criteria provided, single submitter clinical testing The PKHD1 c.3761_3762delCCinsG (p.Ala1254GlyfsTer49) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala1254GlyfsTer49 variant has been reported in six studies and in a total of 18 individuals with autosomal recessive polycystic kidney disease, including in three in a homozygous state, in 14 in a compound heterozygous state, and in one in a heterozygous state (Onuchic et al. 2002; Rossetti et al. 2003; Furu et al. 2003; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). The p.Ala1254GlyfsTer49 variant was absent from 510 control individuals and is not reported in the Exome Aggregation Consortium or Exome Sequencing Project or 1000 Genomes, in a region with good coverage, hence it is presumed to be rare. Based on the collective evidence, the p.Ala1254GlyfsTer49 variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Hadassah Hebrew University Medical Center RCV000169008 SCV000256233 pathogenic Autosomal recessive polycystic kidney disease no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000169008 SCV000784707 not provided Autosomal recessive polycystic kidney disease no assertion provided phenotyping only 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.