ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.11258G>A (p.Arg3753Gln) (rs1555446330)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507238 SCV000604790 likely pathogenic Polycystic kidney disease, adult type 2019-04-22 criteria provided, single submitter clinical testing The c.11758G>A; p.Arg3753Gln variant has been reported in multiple patients diagnosed with autosomal polycystic kidney disease (Cornec-Le Gall 2013, Rossetti 2007, Stekrova 2009). Another missense variant at this residue, p.Arg3753Trp, has also been reported in multiple patients, and is considered likely pathogenic (Audrezet 2012, Cornec-Le Gall 2013, Rossetti 2007). The p.Arg3753Gln variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This arginine at codon 3753 is highly conserved and is located in the polycystin cation channel domain, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, due to a lack of clinical and functional data, the significance of the p.Arg3753Gln variant is uncertain at this time. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013; 24(6):1006-13. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007; 18(7):2143-60. Stekrova J et al. New mutations in the PKD1 gene in Czech population with autosomal dominant polycystic kidney disease. BMC Med Genet. 2009 Aug 17;10:78.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000507238 SCV001251224 uncertain significance Polycystic kidney disease, adult type 2020-02-05 criteria provided, single submitter research PM2, PP3, PP4, PP5
Molecular Biology Laboratory, Fundació Puigvert RCV000507238 SCV001425143 likely pathogenic Polycystic kidney disease, adult type 2020-02-01 criteria provided, single submitter research
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000507238 SCV001427203 likely pathogenic Polycystic kidney disease, adult type 2019-03-25 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_001009944.2(PKD1):c.11258G>A, has been identified in exon 39 of 46 of the PKD1 gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 3753 of the protein (NP_001009944.2(PKD1):p.(Arg3753Gln)). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the PKD channel functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. The variant has been previously described as likely pathogenic and as a VUS, in several patients with polycystic kidney disease (ClinVar, Carrera, P., et al. (2016), Rossetti, S., et al. (2007), Stekrova, J., et al. (2009), Hwang, Y. H., et al. (2016)). Two different variants in the same codon resulting in a change to leucine and tryptophan have also been reported in patients with autosomal dominant polycystic kidney disease (ClinVar, Kim, U. K., et al. (2000), Audrezet, M. P., et al. (2012), Rossetti, S., et al. (2007), Rossetti, S., et al. (2012)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.

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