Submissions for variant NM_000297.4(PKD2):c.958C>T (p.Arg320Ter)

dbSNP: rs749004212

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000703336	SCV000832233	pathogenic	Autosomal dominant polycystic kidney disease	2020-09-11	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with polycystic kidney disease (PMID: 10541293, 10760080, 12707387, 22508176, 23300259, 24374109, 27782177). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562318). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is present in population databases (rs749004212, ExAC 0.006%). This sequence change creates a premature translational stop signal (p.Arg320*) in the PKD2 gene. It is expected to result in an absent or disrupted protein product.
Fulgent Genetics, Fulgent Genetics	RCV001535902	SCV001752538	pathogenic	Polycystic kidney disease 2	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000681764	SCV001782547	pathogenic	not provided	2021-10-29	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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31740684, 12707387, 27782177, 22508176, 25525159, 10541293, 10760080, 23300259, 24374109, 22383692, 17582161, 33141305, 34101167)
PreventionGenetics, part of Exact Sciences	RCV003420205	SCV004113664	pathogenic	PKD2-related condition	2022-09-06	criteria provided, single submitter	clinical testing	The PKD2 c.958C>T variant is predicted to result in premature protein termination (p.Arg320*). This variant was reported in individuals with autosomal dominant polycystic kidney disease (ADPKD) (see for example at Reynolds et al. 1999. PubMed ID: 10541293; Moriyama et al. 2020. PubMed ID: 33141305). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-88959517-C-T). Nonsense variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Gharavi Laboratory, Columbia University	RCV000681764	SCV000809224	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292054	SCV001480721	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg320X variant was identified in 13 of 2820 proband chromosomes (frequency: 0.0046) from individuals or families with autosomal dominant PKD (Audrezet 2012, Hateboer 2000, Hwang 2016, Reynolds 1999, Rossetti 2007, Rossetti 2012, Tan 2008). The variant was also identified in dbSBP (ID: rs749004212) as “NA”,LOVD 3.0, and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in ClinVar, Clinvitae, and PKD1-LOVD databases. The variant was identified in control databases in 1 of 245884 chromosomes at a frequency of 0.000004 in the South Asian population in 1 of 30782 chromosmes (freq. 0.00003) of increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg320X variant leads to a premature stop codon at position 320, 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.