ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.3747T>G (p.Cys1249Trp)

gnomAD frequency: 0.00001  dbSNP: rs748540413
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667920 SCV000792445 uncertain significance Autosomal recessive polycystic kidney disease 2017-06-28 criteria provided, single submitter clinical testing
Invitae RCV000667920 SCV000958909 pathogenic Autosomal recessive polycystic kidney disease 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 1249 of the PKHD1 protein (p.Cys1249Trp). This variant is present in population databases (rs748540413, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11919560, 19914852, 29956005; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552624). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667920 SCV001821394 likely pathogenic Autosomal recessive polycystic kidney disease 2021-08-26 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.3747T>G (p.Cys1249Trp) results in a non-conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251112 control chromosomes (gnomAD and publication data). c.3747T>G has been reported in the literature in individuals affected with autosomal recessive polycystic kidney disease (Ward_2002, Bergmann_2003, Gunay-Aygun_2009, Szabo_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV003236830 SCV003935818 likely pathogenic not provided 2022-12-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11919560, 19914852, 15108277, 29956005, 14741187, 20413436, 12506140, 12925574, 16523049, 15805161, 34573383)
Baylor Genetics RCV003459590 SCV004204569 likely pathogenic Polycystic kidney disease 4 2023-08-26 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003918107 SCV004728894 pathogenic PKHD1-related disorder 2024-02-13 criteria provided, single submitter clinical testing The PKHD1 c.3747T>G variant is predicted to result in the amino acid substitution p.Cys1249Trp. This variant has been reported to be causative for autosomal recessive polycystic kidney disease (ARPKD) (Ward et al. 2002. PubMed ID: 11919560; Gunay-Aygun et al. 2010. PubMed ID: 19914852; Szabó et al. 2018. PubMed ID: 29956005). This variant is reported in 0.0048% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Natera, Inc. RCV000667920 SCV001463309 pathogenic Autosomal recessive polycystic kidney disease 2020-09-16 no assertion criteria provided clinical testing

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.