ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.5134G>A (p.Gly1712Arg) (rs141103838)

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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414198 SCV000340175 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing
Counsyl RCV000373143 SCV000487187 likely pathogenic Autosomal recessive polycystic kidney disease 2016-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000414198 SCV000490722 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The G1712R variant in the PKHD1 gene has been reported previously, along with a second mutation, in an individual with ARPKD (Gunay-Aygun et al., 2010). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports G1712R was observed in 14/8600 alleles from individuals of European background, indicating it may be a rare variant in this population. The G1712R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G1712R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000373143 SCV000545846 likely benign Autosomal recessive polycystic kidney disease 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000373143 SCV000915336 uncertain significance Autosomal recessive polycystic kidney disease 2017-04-27 criteria provided, single submitter clinical testing The PKHD1 c.5134G>A (p.Gly1712Arg) variant has been reported in three studies in which it is found in a compound heterozygous state with a frameshift variant in one individual with polycystic kidney disease (Gunay-Aygun et al. 2010). The p.Gly1712Arg variant was absent from 400 control chromosomes and is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. Therefore, the p.Gly1712Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV001193804 SCV001362923 uncertain significance not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.5134G>A (p.Gly1712Arg) results in a non-conservative amino acid change in 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 0.00074 in 251314 control chromosomes (gnomAD), not present in the homozygous state. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.00074 vs 0.0071), allowing no conclusion about variant significance. The variant, c.5134G>A, has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (Gunay-Aygun_2010, Denamur_2010, Schueler_2016, Bullich_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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x VUS, 2x likely pathogenic). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV000414198 SCV001422396 uncertain significance not provided 2019-01-01 criteria provided, single submitter 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.