Submissions for variant NM_000297.4(PKD2):c.2411G>A (p.Ser804Asn)

gnomAD frequency: 0.00280  dbSNP: rs145343957

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000405309	SCV000343762	benign	not specified	2016-07-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755622	SCV000604829	uncertain significance	not provided	2017-09-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084804	SCV000658972	benign	Autosomal dominant polycystic kidney disease	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157152	SCV001318699	uncertain significance	Polycystic kidney disease 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Athena Diagnostics	RCV000405309	SCV001879479	benign	not specified	2020-12-31	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001157152	SCV003839043	likely benign	Polycystic kidney disease 2	2022-10-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755622	SCV004152960	benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	PKD2: BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292453	SCV001480999	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as “With other allele”, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755622	SCV002035381	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000755622	SCV002038311	uncertain significance	not provided		no assertion criteria provided	clinical testing