ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.4882C>G (p.Pro1628Ala)

dbSNP: rs267601070
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410465 SCV000486843 likely pathogenic Autosomal recessive polycystic kidney disease 2016-08-23 criteria provided, single submitter clinical testing
Mendelics RCV000410465 SCV001137144 pathogenic Autosomal recessive polycystic kidney disease 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410465 SCV003439463 pathogenic Autosomal recessive polycystic kidney disease 2023-05-15 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: 371295). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 19021639, 27225849, 33226606). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267601070, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1628 of the PKHD1 protein (p.Pro1628Ala).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410465 SCV004020378 pathogenic Autosomal recessive polycystic kidney disease 2023-06-12 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.4882C>G (p.Pro1628Ala) results in a non-conservative amino acid change located in an IPT repeat 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 4e-06 in 251422 control chromosomes (gnomAD). c.4882C>G has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease, and most of them reportedly carried a pathogenic variant in trans (e.g. Michel-Calemard_2009, Melchionda_2016, Vaisitti_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003463803 SCV004204636 pathogenic Polycystic kidney disease 4 2023-12-07 criteria provided, single submitter clinical testing

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