Submissions for variant NM_000297.4(PKD2):c.709+1G>A

dbSNP: rs398123308

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078584	SCV000110440	pathogenic	not provided	2012-12-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470757	SCV002768756	pathogenic	Polycystic kidney disease 2	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in-silico tools and affected nucleotide is highly conserved. (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with autosomal dominant polycystic kidney disease (PMID: 9326320, 27499327, 26453610). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV000078584	SCV004025432	likely pathogenic	not provided	2023-02-10	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11438989, 10411676, 9326320, 26453610, 27499327, 26147798)
Invitae	RCV003584550	SCV004293199	likely pathogenic	Autosomal dominant polycystic kidney disease	2023-05-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the PKD2 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 PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 9326320, 26453610, 27499327, 33437033). ClinVar contains an entry for this variant (Variation ID: 92797). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292113	SCV001480945	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 c.709+1G>A variant was identified in 3 of 1910 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Hwang 2016, Veldhuisen 1997). The variant was also identified in dbSNP (ID: rs398123308) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar), the ClinVar database (classified as pathogenic by Emory Genetics), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not found in 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8th 2016). The c.709+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.