ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1748G>A (p.Cys583Tyr)

gnomAD frequency: 0.00001  dbSNP: rs369292828
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809918 SCV000950101 pathogenic Autosomal recessive polycystic kidney disease 2023-10-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 583 of the PKHD1 protein (p.Cys583Tyr). This variant is present in population databases (rs369292828, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease (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: 654032). 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) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000809918 SCV000996557 uncertain significance Autosomal recessive polycystic kidney disease 2019-05-21 criteria provided, single submitter clinical testing
Mendelics RCV000809918 SCV001137148 likely pathogenic Autosomal recessive polycystic kidney disease 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117601 SCV003801267 uncertain significance not specified 2023-01-17 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.1748G>A (p.Cys583Tyr) 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 4e-06 in 251060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1748G>A in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: two submitters classified the variant as uncertain significance and two classified the variant as likely pathogenic without providing evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000809918 SCV002081064 uncertain significance Autosomal recessive polycystic kidney disease 2018-12-18 no assertion criteria provided clinical testing

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