ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.1320G>T (p.Arg440Ser) (rs886041114)

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Total submissions: 2
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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 2019-07-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 440 of the PKD2 protein (p.Arg440Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal dominant polycystic kidney disease (PMID: 20950398, 23300259, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20950398). For these reasons, this variant has been classified as Pathogenic.

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