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

dbSNP: rs886061623

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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	2023-11-05	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. 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 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. 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.
GeneDx	RCV003225063	SCV003921662	pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Identified in patients with autosomal recessive polycystic kidney disease (ARPKD) in published literature (Losekoot et al., 2005); however, the inclusion criteria for the study was unclear; Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16133180)
Natera, Inc.	RCV000315696	SCV001463323	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing