ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.1831C>T (p.Arg611Trp) (rs1555458413)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757623 SCV000885922 likely pathogenic Polycystic kidney disease, adult type 2018-11-17 criteria provided, single submitter clinical testing The PKD1 c.1831C>T; p.Arg611Trp variant is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Audrezet 2012, Cornec Le-Gall 2013, Garcia-Gonzalez 2007). This variant is reported as likely pathogenic in ClinVar (Variation ID: 433949) and the Mayo ADPKD variant database, and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 611 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on its occurrence in multiple individuals clinically diagnosed with autosomal dominant polycystic kidney disease, the p.Arg611Trp variant is considered to be likely pathogenic. References: Link to Mayo ADPKD variant database: 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. Garcia-Gonzalez M et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007; 92(1-2):160-7.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000757623 SCV001251181 uncertain significance Polycystic kidney disease, adult type 2020-02-05 criteria provided, single submitter research PM2, PP3, PP4, PP5
Molecular Biology Laboratory, Fundació Puigvert RCV000757623 SCV001425167 likely pathogenic Polycystic kidney disease, adult type 2020-02-01 criteria provided, single submitter research
Athena Diagnostics Inc RCV001288337 SCV001475358 uncertain significance not provided 2019-11-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501282 SCV000592740 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 .Arg611Trp variant was identified in 4 of 1564 proband chromosomes (frequency: 0.003) from individuals or families with Autosomal Dominant Polycystic Kidney Disease based on standard ultrasound criteria (Audrézet 2012, Garcia-Gonzalez 2007). The variant was also identified in the ADPKD Mutation Database (as “likely pathogenic”). The variant was not found in dbSNP, the Exome Aggregation Consortium database (March 14 2016), Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The p.Arg611 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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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