Submissions for variant NM_000297.4(PKD2):c.1094+3_1094+6del

dbSNP: rs1553925470

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000697098	SCV000825689	likely pathogenic	Autosomal dominant polycystic kidney disease	2020-01-07	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 12707387, 30333007, 29529603). The variant is also known as IVS4+3del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 434014). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 4 of the PKD2 gene. It does not directly change the encoded amino acid sequence of the PKD2 protein, but it affects a nucleotide within the consensus splice site of the intron. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Eurofins Ntd Llc (ga)	RCV000728620	SCV000856217	pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001041	SCV001158156	pathogenic	Polycystic kidney disease 2	2019-01-29	criteria provided, single submitter	clinical testing	The PKD2 c.1094+3_1094+6delAAGT variant has been described in multiple individuals and families affected with autosomal dominant polycystic kidney disease (ADPKD; see link to Mayo database, He 2018, Magistroni 2003, Rossetti 2007, Rossetti 2012). It contains an entry in ClinVar (Variation ID: 434014) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes four nucleotides of the consensus splice donor site within intron 4, and RNA studies have demonstrated a loss of the canonical splice donor site and incorporation of intron 4 into the sequence (Rossetti 2007). Based on available information, this variant is considered pathogenic. REFERENCES Link to Mayo ADPKD database: http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?GENE=PKD2&apkd_mode=PROD He W et al. Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction. BMC Med Genet. 2018 Oct 17;19(1):186. Magistroni R et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003 May;14(5):1164-74. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33.
Fulgent Genetics, Fulgent Genetics	RCV001001041	SCV002810877	pathogenic	Polycystic kidney disease 2	2021-09-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002524141	SCV003745385	pathogenic	Inborn genetic diseases	2022-11-29	criteria provided, single submitter	clinical testing	The c.1094+3_1094+6delAAGT variant results from a deletion of 4 nucleotides between positions c.1094+3 and c.1094+6 after coding exon 4 of the PKD2 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in several individuals with autosomal dominant polycystic kidney disease (Magistroni, 2003; Tan, 2009; Rossetti, 2012; He, 2018; Xu, 2018; Xu, 2021). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000728620	SCV004170065	likely pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Published functional studies detect an altered transcript retaining all or a portion of intron 4 in a patient with the variant (Rossetti et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 12707387, 30333007, 29529603, 18837007, 34101167, 35778421, 22383692, 17582161)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502098	SCV000592878	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 c.1094+3_1094+6delAAGT variant was identified in 8 of 1056 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Magistroni 2003, Tan 2009, Rossetti 2007, Rossetti 2012). Rosetti et al (2007) used RT-PCR analysis on lymphoblast cell lines to show that the variant abolished the normal donor site and the deletion produced a product that incorporated all or part of IVS4 into the sequence. In silico splicing models also confirm a splicing defect in a study characterizing the pathogenic potential of unclassified variants (Tan 2009). The variant was identified in the ADPKD Mutation Database (classification highly likely pathogenic), but was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight COGR, PKD2-LOVD, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, or in the Exome Aggregation Consortium database (March 14, 2016). The c.1094+3_1094+6delAAGT variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing, predicting the abolishment of the 5’ consensus splice site. The variant is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.