Submissions for variant NM_000297.4(PKD2):c.2407C>T (p.Arg803Ter)

dbSNP: rs778235410

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756535	SCV000884370	pathogenic	Polycystic kidney disease 2	2019-01-07	criteria provided, single submitter	clinical testing	The PKD2 c.2407C>T; p.Arg803Ter variant (rs778235410) has been reported in multiple individuals diagnosed with autosomal dominant polycystic kidney disease (Audrezet 2012, Chung 2006, Deltas 2001, Mallawaarachchi 2016, Tan 2011, Zhang 2005). It is observed on only three chromosomes in the Genome Aggregation Database (3/251064 alleles), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg803Ter variant is considered to be pathogenic. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Chung W et al. PKD2 gene mutation analysis in Korean autosomal dominant polycystic kidney disease patients using two-dimensional gene scanning. Clin Genet. 2006; 70(6):502-8. Deltas C et al. Mutations of the human polycystic kidney disease 2 (PKD2) gene. Hum Mutat. 2001; 18(1):13-24. Mallawaarachchi AC et al. Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur J Hum Genet. 2016 Nov;24(11):1584-1590. Tan Y et al. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet. 2011; 80(3):287-92. Zhang S et al. Mutation analysis of autosomal dominant polycystic kidney disease genes in Han Chinese. Nephron Exp Nephrol. 2005; 100(2):e63-76.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249119	SCV001422341	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001249119	SCV001788093	pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25491204, 15717641, 33437033, 32533764, 27165007, 17100995, 22508176, 31740684, 25525159, 11438989, 21115670, 20950398, 15775720, 32361310, 34101167, 29055226, 30639418)
MGZ Medical Genetics Center	RCV000756535	SCV002580454	pathogenic	Polycystic kidney disease 2	2021-10-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000756535	SCV002768094	pathogenic	Polycystic kidney disease 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variant have been reported as pathogenic in many individuals with polycystic kidney disease (PKD) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in multiple families with PKD, including one individual with sinus bradycardia and other cardiac anomalies (ClinVar, pkdb, PMID: 30639418, PMID: 25491204). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000756535	SCV002810389	pathogenic	Polycystic kidney disease 2	2022-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV002533792	SCV003494566	pathogenic	Autosomal dominant polycystic kidney disease	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg803*) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is present in population databases (rs778235410, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 31740684). ClinVar contains an entry for this variant (Variation ID: 618321). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292538	SCV001480747	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg803X variant was identified in 1 of 40 proband chromosomes (frequency: 0.025) from individuals or families in the Korean population with ADPKD (Choi 2014). The variant was also identified in dbSNP (ID: rs778235410) as “NA”. The variant was also identified in the genome Aggregation Database (February 27, 2017) in 3 of 121234 chromosomes (freq. 0.00001) and the Exome Aggregation Consortium database (August 8th 2016) in 3 of 121234 chromosomes (freq. 0.00002) in the East Asian population in 3 of 8590 chromosomes (freq. 0.0003), but was not seen in the African, Finnish, European (Non-Finnish), Latino, South Asian or other populations. The variant was not identified in the 1000 Genomes and the NHLBI GO Exome Sequencing Projects nor in the Clinvitae, the ClinVar, GeneInsight COGR, ADPKD Mutation Database, and PKD2-LOVD databases. The p.Arg803X variant leads to a premature stop codon at position 803, which 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.