Submissions for variant NM_138694.4(PKHD1):c.1964+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1385712943

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001248507	SCV001421999	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 20 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 clinical features of polycystic kidney disease (PMID: 36065636; Invitae). 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: 972469). 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	RCV001331697	SCV001523793	pathogenic	Polycystic kidney disease 4	2019-11-13	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248507	SCV004804167	likely pathogenic	Autosomal recessive polycystic kidney disease	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.1964+1G>T 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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250918 control chromosomes (gnomAD). c.1964+1G>T has been reported in the literature in the compound heterozygous state in an individual with clinical features of Polycystic Kidney And Hepatic Disease who also suffered recurrent vascular ischemic strokes (Kumar_2022). These data suggest the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36065636). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001248507	SCV002081052	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-03-03	no assertion criteria provided	clinical testing