ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8554+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1790925351
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Revvity Omics, Revvity RCV001784844 SCV002018823 pathogenic Polycystic kidney disease 4 2020-02-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002544253 SCV003439441 likely pathogenic Autosomal recessive polycystic kidney disease 2024-02-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 54 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with polycystic kidney disease (PMID: 27225849). ClinVar contains an entry for this variant (Variation ID: 1323461). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002544253 SCV003928691 likely pathogenic Autosomal recessive polycystic kidney disease 2023-04-06 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.8554+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248318 control chromosomes. c.8554+1G>A has been reported in the literature in at least one individual affected with Autosomal Recessive Polycystic Kidney Disease (e.g., Melchionda_2016). 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. Two ClinVar submitters (evaluation after 2014) have cited the variant, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV001784844 SCV005056278 pathogenic Polycystic kidney disease 4 2024-03-24 criteria provided, single submitter clinical testing

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