Submissions for variant NM_000297.4(PKD2):c.1249C>T (p.Arg417Ter)

gnomAD frequency: 0.00001  dbSNP: rs1324209174

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Gharavi Laboratory, Columbia University	RCV000681683	SCV000809130	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Blueprint Genetics	RCV000681683	SCV000928278	pathogenic	not provided	2019-03-15	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV001281322	SCV001425211	pathogenic	Polycystic kidney disease 2	2020-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861899	SCV002134036	pathogenic	Autosomal dominant polycystic kidney disease	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg417*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 9773786, 31740684). ClinVar contains an entry for this variant (Variation ID: 562248). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV001281322	SCV002581244	pathogenic	Polycystic kidney disease 2	2021-11-08	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001861899	SCV002756459	likely pathogenic	Autosomal dominant polycystic kidney disease	2022-11-20	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001281322	SCV002766763	pathogenic	Polycystic kidney disease 2	2022-03-31	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 (v2, v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are a large number of NMD-predicted variants that have been identified in affected individuals and classified as likely pathogenic or pathogenic (ClinVar, PMID: 28356211). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with autosomal dominant polycystic kidney disease (ClinVar, ADPKD variant database, PMIDs: 28356211, 33964006). (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	RCV001281322	SCV002793363	pathogenic	Polycystic kidney disease 2	2024-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000681683	SCV002820762	pathogenic	not provided	2022-08-18	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9773786, 31740684, 33532864, 30820006, 10760080, 10411676, 34101167, 33964006, 11007674, 15775720, 22508176, 26453610, 22383692, 21115670)
Athena Diagnostics	RCV000681683	SCV004229854	pathogenic	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.
CeGaT Center for Human Genetics Tuebingen	RCV000681683	SCV005092610	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKD2: PVS1, PM2, PM6, PS4:Moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001281322	SCV005418907	pathogenic	Polycystic kidney disease 2		criteria provided, single submitter	clinical testing	PM2+PS4+PP1_Strong+PVS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292055	SCV001480722	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg417* variant was identified in 17 of 2768 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD (Audrezet 2012, Hoefele 2011, Hwang 2016, Pei 1998, Rossetti 2012, Torra 1999, Torra 2000, Zhang 2004). The variant was also identified in ClinVar (classified as pathogenic by Gharavi Laboratory, Columbia University), LOVD 3.0 (2x), and in ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, or PKD1-LOVD. The variant was identified in control databases in 1 of 245880 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 15300 chromosomes (freq: 0.00007), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.1249C>T variant leads to a premature stop codon at position 417 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 ADPKD 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000681683	SCV001928943	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000681683	SCV001960121	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000681683	SCV002036724	pathogenic	not provided		no assertion criteria provided	clinical testing