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

dbSNP: rs778896252

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869022	SCV002202882	uncertain significance	Autosomal dominant polycystic kidney disease	2024-10-26	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). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PKD2 function (PMID: 27071085, 37028763). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000756537	SCV005410563	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	BS1, PP1, PM4
Fulgent Genetics, Fulgent Genetics	RCV005047014	SCV005668047	uncertain significance	Polycystic kidney disease 2	2024-03-02	criteria provided, single submitter	clinical testing
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.