ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8642+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1485161784
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781719 SCV000919986 pathogenic Autosomal recessive polycystic kidney disease 2017-10-13 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.8642+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/243188 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Multiple publications have cited the variant in affected compound heterozygote patients (Gunay-Aygun_2010, Sgro_2004, Denamur_2010) . Multiple databases have cited the variant as "disease-causing/likely pathogenic." Taken together, this variant is classified as pathogenic.
Molecular Biology Laboratory, Fundació Puigvert RCV000781719 SCV001425241 pathogenic Autosomal recessive polycystic kidney disease 2020-02-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000781719 SCV002231787 pathogenic Autosomal recessive polycystic kidney disease 2022-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 55 of the PKHD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with polycystic kidney disease (PMID: 14971004, 19940839). 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: 633352). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003461058 SCV004204705 pathogenic Polycystic kidney disease 4 2023-03-21 criteria provided, single submitter clinical testing
Natera, Inc. RCV000781719 SCV002077973 pathogenic Autosomal recessive polycystic kidney disease 2017-11-10 no assertion criteria provided clinical testing

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