Submissions for variant NM_138694.4(PKHD1):c.8555-2A>C

gnomAD frequency: 0.00001  dbSNP: rs1020621286

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492982	SCV000582474	pathogenic	not provided	2015-09-07	criteria provided, single submitter	clinical testing	The c.8555-2A>C variant in the PKHD1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 54. It is predicted to cause abnormal gene splicing, either leading to abnormal message subject to nonsense-mediated mRNA decay, or an abnormal protein product if the message is used for protein translation. The c.8555-2A>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.8555-2A>C as a pathogenic variant.
Baylor Genetics	RCV001004192	SCV001163025	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Invitae	RCV001004192	SCV001227408	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-06-14	criteria provided, single submitter	clinical testing	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. Studies have shown that disruption of this splice site results in skipping of exon 55 and introduces a premature termination codon (PMID: 34536170). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 429814). Disruption of this splice site has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 34008892, 34536170). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 54 of the PKHD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000492982	SCV001468095	pathogenic	not provided	2020-09-23	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001775124	SCV002012478	pathogenic	Polycystic kidney disease 4	2014-10-13	criteria provided, single submitter	research	ACMG codes: PVS1; PM2; PP5
Fulgent Genetics, Fulgent Genetics	RCV001775124	SCV002783350	likely pathogenic	Polycystic kidney disease 4	2022-05-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419833	SCV004118261	pathogenic	PKHD1-related disorder	2023-01-04	criteria provided, single submitter	clinical testing	The PKHD1 c.8555-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the compound heterozygous state in a patient with polycystic kidney disease and in vitro (minigene assay) results in exon skipping (Ishiko S et al. 2022. PubMed ID: 34536170). 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 acceptor site in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV001775124	SCV004204584	pathogenic	Polycystic kidney disease 4	2023-08-14	criteria provided, single submitter	clinical testing