Submissions for variant NM_000297.4(PKD2):c.1320G>T (p.Arg440Ser)

dbSNP: rs886041114

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002301	SCV001160187	likely pathogenic	Polycystic kidney disease 2	2018-12-24	criteria provided, single submitter	clinical testing	The PKD2 c.1320G>T; p.Arg440Ser variant is reported in the literature in several individuals affected with autosomal dominant polycystic kidney disease (Neumann 2012, Tan 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a moderately conserved nucleotide at the first nucleotide of exon 6, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Consistent with these predictions, RNA analyses indicate increased skipping of exon 6 and decreased levels of mature PKD2 transcript in cells from an affected individual with this variant (Tan 2011). Based on available information, this variant is considered to be likely pathogenic. References: Neumann HP et al. Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes. Int Urol Nephrol. 2012 Dec;44(6):1753-62. Tan YC et al. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet. 2011 Sep;80(3):287-92.
Invitae	RCV001221367	SCV001393408	pathogenic	Autosomal dominant polycystic kidney disease	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 440 of the PKD2 protein (p.Arg440Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 20950398, 23300259; Invitae). ClinVar contains an entry for this variant (Variation ID: 811865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (PMID: 20950398). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV001002301	SCV002580821	likely pathogenic	Polycystic kidney disease 2	2022-04-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001002301	SCV002785896	likely pathogenic	Polycystic kidney disease 2	2022-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV003148910	SCV003836942	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	This variant is demonstrated to destroy the canonical splice acceptor site and result in loss of function (Tan et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26692149, 20950398, 22367170, 33639313)
CeGaT Center for Human Genetics Tuebingen	RCV003148910	SCV003916901	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PKD2: PM2, PS4:Moderate, PP3, PP4, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002301	SCV003934435	likely pathogenic	Polycystic kidney disease 2	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: PKD2 c.1320G>T (p.Arg440Ser) results in a non-conservative amino acid change located in the Polycystin domain (IPR046791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 5' donor site at the canonical 3' acceptor site. Experimental evidence evaluating mRNA from patient leukocytes confirmed these predictions, showing the variant results in transcripts that skip exon 6 (Tan_2011). The variant was absent in 251286 control chromosomes (gnomAD). c.1320G>T has been reported in the literature in individuals affected with Polycystic Kidney Disease 2 (e.g. Tan_2011, Neumann_2012, Nielsen_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22367170, 33639313, 20950398). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.