Submissions for variant NM_138694.4(PKHD1):c.6332+2T>A

dbSNP: rs1783090781

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251457	SCV001427100	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-21	criteria provided, single submitter	clinical testing	A heterozygous canonical splice-site variant, NM_138694.3(PKHD1):c.6332+2T>A, has been identified in intron 38 of 66 of the PKHD1 gene. The variant is likely to cause a splice defect, resulting in frameshift and likely causing non-sense mediated decay. The nucleotide at this position has very high conservation (Phylop UCSC). This nucleotide substitution is predicted to cause aberrant splicing and may result in a truncated protein; further testing via RNA studies are required to confirm if splicing is altered. The variant is absent in population databases (gnomAD, dbSNP, 1000G), and has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE.
PreventionGenetics, part of Exact Sciences	RCV003399026	SCV004110452	pathogenic	PKHD1-related disorder	2023-01-27	criteria provided, single submitter	clinical testing	The PKHD1 c.6332+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in an individual with polycystic kidney disease (Patient P002 in Supplemental Table 2, Jayasinghe et al. 2021. PubMed ID: 32939031). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.