Submissions for variant NM_000297.4(PKD2):c.2533C>T (p.Arg845Ter)

gnomAD frequency: 0.00001  dbSNP: rs369678636

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627205	SCV000748192	pathogenic	not provided	2022-02-24	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: 25525159, 33532864, 24658975, 30369598, 27782177, 22863349, 11007674, 22008521, 22383692, 11438989, 22508176)
Gharavi Laboratory, Columbia University	RCV000627205	SCV000809223	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000763530	SCV000894342	pathogenic	Polycystic kidney disease 2	2024-02-25	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000763530	SCV001425216	pathogenic	Polycystic kidney disease 2	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000763530	SCV002767485	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) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in individuals with ADPKD (ClinVar, PMID: 22863349, 24658975). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529806	SCV003525700	pathogenic	Autosomal dominant polycystic kidney disease	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg845*) 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 (rs369678636, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 11007674, 24658975). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523770). For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763530	SCV005416503	pathogenic	Polycystic kidney disease 2		criteria provided, single submitter	clinical testing	PM2+PS4_Moderate+PP1_Strong+PVS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292154	SCV001480731	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg845* variant was identified in 11 of 458 proband chromosomes (frequency: 0.02) from individuals or families with Autosomal Dominant Polycystic Kidney Disease (Virzi 2014, Robinson 2012, Magistroni 2003). The variant was also identified in dbSNP (ID: rs369678636) as “NA”, ClinVar (classified as pathogenic by GeneDx and Gharavi Laboratory, Columbia University), and in ADPKD Mutation Database (as definitely pathogenic). The variant was identified in control databases in 3 of 245930 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 33574 chromosomes (freq: 0.00006), European in 1 of 111414 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other, and South Asian populations. The variant was not identified in PKD2-LOVD. The variant was reported as a possible founder mutation in the Italian population by Virzi 2014. The c.2533C>T variant leads to a premature stop codon at position 845, 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.
PreventionGenetics, part of Exact Sciences	RCV004752975	SCV005362920	pathogenic	PKD2-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The PKD2 c.2533C>T variant is predicted to result in premature protein termination (p.Arg845*). This variant has been reported to be pathogenic for autosomal dominant polycystic kidney disease (ADPKD) (Torra et al. 2000. PubMed ID: 11007674; Virzì et al. 2014. PubMed ID: 24658975). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic.