ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.390+1G>T (rs752327566)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780595 SCV000917995 likely pathogenic Autosomal recessive polycystic kidney disease 2017-09-22 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.390+1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict the complete loss of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5/215750 control chromosomes at a frequency of 0.0000232, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). The variant was reported in one affected individual (Furu_2003). Taken together, this variant is classified as likely pathogenic.
Blueprint Genetics RCV000788977 SCV000928285 likely pathogenic not provided 2019-03-20 criteria provided, single submitter clinical testing
Invitae RCV000780595 SCV000931542 likely pathogenic Autosomal recessive polycystic kidney disease 2019-09-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the PKHD1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs752327566, ExAC 0.004%). This variant has been observed in an individual with clinical features of polycystic kidney disease (PMID: 12874454). This variant is also known as IVS5+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 632942). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). 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.

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