ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1233+1G>A (rs886061623)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000315696 SCV000464120 uncertain significance Autosomal recessive polycystic kidney disease 2016-08-27 criteria provided, single submitter clinical testing The PKHD1 c.1233+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1233+1G>A variant was detected in two families with autosomal recessive polycystic kidney disease, including in a compound heterozygous state with a pathogenic missense variant in one individual and in a heterozygous state in one individual in whom the second variant could not be identified (Losekoot et al. 2005). Control data are not available for this variant, and it is not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage. Therefore, the variant is presumed to be rare. Due to the potential impact of splice donor variants and the limited available evidence, the c.1233+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV000315696 SCV001163070 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Invitae RCV000315696 SCV001200698 likely pathogenic Autosomal recessive polycystic kidney disease 2019-03-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 of the PKHD1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal recessive polycystic kidney disease (PMID: 16133180). ClinVar contains an entry for this variant (Variation ID: 357452). 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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