Submissions for variant NM_000297.4(PKD2):c.2159dup (p.Asn720fs)

dbSNP: rs757757289

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254204	SCV001430273	pathogenic	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000014477	SCV001752487	pathogenic	Polycystic kidney disease 2	2022-05-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001559801	SCV001782100	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26453610, 22508176, 30333007, 9573526, 30820006, 31317121, 17574468, 12707387, 9773786, 17582161, 31740684, 33437033)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014477	SCV002767045	pathogenic	Polycystic kidney disease 2	2022-06-24	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 <0.001 for a dominant condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least five individuals with polycystic kidney disease (ClinVar; PMID: 9573526, 30333007). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002513045	SCV003595099	pathogenic	Inborn genetic diseases	2021-11-24	criteria provided, single submitter	clinical testing	The c.2159dupA (p.N720Kfs*5) alteration, located in exon 11 (coding exon 11) of the PKD2 gene, consists of a duplication of A at position 2159, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several patients with autosomal dominant polycystic kidney disease and co-segregated with disease in one large family (Pei, 1998; Rossetti, 2007; He, 2018; Kim, 2019; Lanktree, 2019; Sekine, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Invitae	RCV001254204	SCV004293201	pathogenic	Autosomal dominant polycystic kidney disease	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn720Lysfs*5) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 30333007). ClinVar contains an entry for this variant (Variation ID: 13522). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000014477	SCV000034728	pathogenic	Polycystic kidney disease 2	1998-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292200	SCV001480951	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Asn720Lysfs*5 variant was identified in 5 of 2800 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD, and was not identified in 400 control chromosomes from healthy individuals (Audrezet 2012, Magistroni 2003, Rossetti 2007). The variant was further identified in the ADPKD Mutation Database as definitely pathogenic. The variant was not identified in dbSNP, the 1000 Genomes, NHLBI Exome Sequencing Projects, the Exome Aggregation Consortium (August 8, 2016), the PKD2-LOVD, Clinvitae, ClinVar and COGR databases. The c.2159dupA variant is predicted to cause a frameshift, which alters the protein amino acid sequence beginning at codon 720 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in 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 one study the variant was described in a family with PKD and segregated with disease in all family members tested (5 affected individuals were positive and 5 >50year old unaffected individuals were negative). The variant was determined to be causative of ADPKD and to produce a truncated polycystin 2 lacking the EF-hand domain, resulting in a protein that would not bind calcium. Furthermore, the variant is also predicted to produce a truncated protein lacking both the cytoplasmic domains required for polycystin 2 to interact with polycystin 1 and with itself (Pei 1998). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001559801	SCV003839867	pathogenic	not provided	2022-08-26	no assertion criteria provided	clinical testing	DNA sequence analysis of the PKD2 gene demonstrated a single base pair duplication in exon 11, c.2159dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 4 amino acids downstream of the change, p.Asn720Lysfs*5. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PKD2 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.0008% in the overall population (dbSNP rs757757289). This pathogenic sequence change has previously been described in several individuals with autosomal dominant polycystic kidney disease (PMID: 31740684, 31317121, 33437033, 30820006). This variant was found to segregate with disease in five members of an ADPKD family and was absent from unaffected members of the family (PMID: 9573526). Based on these collective evidences, this sequence change is classified as pathogenic.