ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.4187C>T (p.Pro1396Leu)

dbSNP: rs1581809655
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000995603 SCV001149877 likely pathogenic Autosomal recessive polycystic kidney disease 2018-06-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000995603 SCV001216436 pathogenic Autosomal recessive polycystic kidney disease 2022-06-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 807463). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 32359821; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1396 of the PKHD1 protein (p.Pro1396Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526792 SCV005039874 uncertain significance not specified 2024-03-17 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.4187C>T (p.Pro1396Leu) results in a non-conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4187C>T has been reported in the literature in at least one individual affected with Polycystic Kidney Disease (e.g., Reidhammer_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32359821). ClinVar contains an entry for this variant (Variation ID: 807463). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000995603 SCV002080964 uncertain significance Autosomal recessive polycystic kidney disease 2020-10-15 no assertion criteria provided clinical testing

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