Submissions for variant NM_000297.4(PKD2):c.916C>T (p.Arg306Ter)

dbSNP: rs200001068

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000449565	SCV000537693	pathogenic	Polycystic kidney disease 2	2016-07-12	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681703	SCV000809155	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000449565	SCV001368854	pathogenic	Polycystic kidney disease 2	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000681703	SCV001422338	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000449565	SCV001425219	pathogenic	Polycystic kidney disease 2	2020-02-01	criteria provided, single submitter	research
Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen	RCV000449565	SCV001750073	pathogenic	Polycystic kidney disease 2	2021-06-17	criteria provided, single submitter	clinical testing	The change is listed in the dbSNP database (dbSNP151, as of June 17, 2021) with the rs number rs200001068. In gnomAD it is reported with a frequency of 0.0003981% (1/251172) (as of June 17, 2021). The variant is mentioned as pathogenic both in ClinVar (including RCV000449565.3) and in the renowned PKD mutation database (http://pkd.mayo.edu; as of June 17, 2021). The variant has been described several times in the literature in patients with ADPKD (including Audrézet et al., 2012). In the case of stop or nonsense variants in a gene that matches the phenotype, there is also a high probability of pathogenic relevance. At this point in time, the variant is to be regarded as a "pathogenic variant" (ACMG criteria).
Invitae	RCV001861649	SCV002240561	pathogenic	Autosomal dominant polycystic kidney disease	2021-10-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 397507). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 9326320, 29529603). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg306*) 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).
GeneDx	RCV000681703	SCV002520136	pathogenic	not provided	2021-12-02	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, 24113780, 31589614, 33532864, 29633482, 31740684, 9326320, 29529603, 33437033, 16430766, 14993477, 23300259, 32970388, 18837007, 11968093, 24374109, 10760080)
Athena Diagnostics Inc	RCV000681703	SCV002771629	pathogenic	not provided	2021-06-30	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000681703	SCV004226766	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	PP1, PM2_supporting, PS4_moderate, PVS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292151	SCV001480728	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg306* variant was identified in 13 of 3960 proband chromosomes (frequency: 0.003) from individuals or families with autosomal dominant polycystic kidney disease (ADPKD; Audrezet 2012, Garcia-Gonzalez 2007, Magistroni 2003, Reiterova 2002, Rossetti 2007, Rossetti 2012, Stekrova 2004, Tan 2008, Torra 2000, Veldhuisen 1997, Vouk 2006). The variant was also identified in ClinVar (classified as pathogenic by Center of Genomic Medicine Geneva and Gharavi Laboratory at Columbia University), LOVD 3.0 (3x), and 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 245930 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111434 chromosomes (freq: 0.000009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.916C>T variant leads to a premature stop codon at position 306, 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.