ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.4292G>A (p.Cys1431Tyr)

gnomAD frequency: 0.00004  dbSNP: rs753307105
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000328052 SCV000340904 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing
Invitae RCV000675159 SCV000948834 pathogenic Autosomal recessive polycystic kidney disease 2022-10-15 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 1431 of the PKHD1 protein (p.Cys1431Tyr). This variant is present in population databases (rs753307105, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 27225849; 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: 287201). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000675159 SCV001821332 pathogenic Autosomal recessive polycystic kidney disease 2021-08-20 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.4292G>A (p.Cys1431Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three 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-05 in 251122 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (4e-05 vs 0.0071), allowing no conclusion about variant significance. c.4292G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Krall_2014, Melchionda_2016, Dafinger_2020, Burgmaier_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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003391051 SCV004121324 pathogenic PKHD1-related disorder 2023-04-07 criteria provided, single submitter clinical testing The PKHD1 c.4292G>A variant is predicted to result in the amino acid substitution p.Cys1431Tyr. In the compound heterozygous (with different truncating pathogenic variants) or homozygous state, this variant has been repeatedly reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Burgmaier et al. 2021. PubMed ID: 33940108, supplementary data; Dafinger et al. 2020. PubMed ID: 33112055; Melchionda et al. 2016. PubMed ID: 27225849). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51890316-C-T). This variant is interpreted as pathogenic.
Baylor Genetics RCV003475914 SCV004202202 likely pathogenic Polycystic kidney disease 4 2023-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000675159 SCV000800776 likely pathogenic Autosomal recessive polycystic kidney disease 2019-06-09 no assertion criteria provided clinical testing
Natera, Inc. RCV000675159 SCV001459201 likely pathogenic Autosomal recessive polycystic kidney disease 2020-09-16 no assertion criteria provided clinical testing

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