ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.10043G>A (p.Arg3348Gln)

gnomAD frequency: 0.00044  dbSNP: rs146494724
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516396 SCV000614457 uncertain significance not specified 2016-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764033 SCV000894987 uncertain significance Polycystic kidney disease, adult type 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV002469179 SCV002765713 uncertain significance not provided 2022-12-12 criteria provided, single submitter clinical testing Identified in unrelated patients with polycystic kidney disease in published literature (Bataille et al., 2011; Chang et al., 2013; Cornec-Le Gall et al., 2013); 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: 23431072, 22008521, 23985799, 29801666, 31514750)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000516396 SCV003934668 uncertain significance not specified 2023-05-26 criteria provided, single submitter clinical testing Variant summary: PKD1 c.10043G>A (p.Arg3348Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 186804 control chromosomes, predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), suggesting that the variant could be a benign polymorphism found primarily in populations of Non-Finnish European origin, yet this should be interpreted with caution due to the presence of the PKD1 pseudogene. c.10043G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 1 (e.g. Bataille_2011, Chang_2013, Cornec-LeGall_2013, Carrera_2016, Bullich_2018). However, this also includes cases where it was found in individuals with other PKD1 variants, including a truncating variant (PKD1 c.1960C>T, p.Arg654X; Chang_2013) and a pathogenic variant in PKD2 (PKD2 c.1094+1G>A; Carrera_2016), providing supporting evidence for a benign role. Thus, these reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26139440, 22008521, 29801666, 27499327, 23985799, 23431072). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breakthrough Genomics, Breakthrough Genomics RCV002469179 SCV005194123 uncertain significance not provided criteria provided, single submitter not provided
PreventionGenetics, part of Exact Sciences RCV004740296 SCV005361228 uncertain significance PKD1-related disorder 2024-06-17 no assertion criteria provided clinical testing The PKD1 c.10043G>A variant is predicted to result in the amino acid substitution p.Arg3348Gln. This variant has been reported as a variant of uncertain significance in multiple individuals with polycystic kidney disease (see, for example, Chang et al. 2013. PubMed ID: 23985799; Cornec-Le Gall et al. 2013. PubMed ID: 23431072; Carrera et al. 2016. PubMed ID: 27499327). However, this variant is also reported in 0.065% of alleles in individuals of African descent in gnomAD, which is higher than expected for a fully penetrant pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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