ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.2208_2213del (p.Leu736_Asn737del)

dbSNP: rs778896252
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756537 SCV000884372 likely pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing
Invitae RCV001869022 SCV002202882 uncertain significance Autosomal dominant polycystic kidney disease 2023-12-18 criteria provided, single submitter clinical testing This variant, c.2208_2213del, results in the deletion of 2 amino acid(s) of the PKD2 protein (p.Leu736_Asn737del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs778896252, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 14993477, 33168999). ClinVar contains an entry for this variant (Variation ID: 618322). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000756537 SCV002504002 uncertain significance not provided 2022-04-12 criteria provided, single submitter clinical testing Identified in an individual with end stage renal disease and liver cysts and her daughter with renal cysts and normal renal function in published literature (Stekrova et al., 2004); In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27071085, 31589614, 14993477)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235381 SCV003934433 uncertain significance not specified 2023-05-10 criteria provided, single submitter clinical testing Variant summary: PKD2 c.2208_2213delAAACTT (p.Leu736_Asn737del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 9.9e-05 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PKD2 causing Polycystic Kidney Disease 2 (9.9e-05 vs 0.00013), allowing no conclusion about variant significance. c.2208_2213delAAACTT has been reported in the literature in an individual reportedly affected with features of polycycstic kidney disease (Strekov_2004). It has subsequently been reported in one case from a cohort of very early onset polycystic kidney disease with a co-occurring pathogenic variant in the PKD1 gene and a different paternal PKD2 variant that was inherited from an unaffected father (example, Durkie_2021). This variant and the pathogenic PKD1 variant were inherited from an affected mother. At-least one co-occurrence with another pathogenic variant(s) have been reported as summarized above (Durkie_2021, PKD1 c.11713-2A>T), providing supporting evidence for a benign role. To our knowledge, digenic inheritance of PKD1 and PKD2 variants has not been confirmed as a disease association. Therefore, these data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, Arif Pavel_2016, Petri_2010). The following publications have been ascertained in the context of this evaluation (PMID: 27071085, 28356211, 33168999, 20439752, 14993477). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (LP, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Gharavi Laboratory, Columbia University RCV000756537 SCV000920753 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292008 SCV001481059 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 p.Leu736_Asn737del variant was identified in 1 of 230 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD and segregated with disease in multiple affected family members (Stekrova 2004). The variant was also identified in dbSNP (ID: rs778896252), LOVD 3.0 (2x ), and in ADPKD Mutation Database (as Highly Likely Pathogenic). The variant was not identified in ClinVar, or PKD1-LOVD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a Leucine (Leu) and Asparagine (Asn) residue at codon 736 and 737; the impact of this alteration on PKD2 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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