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

dbSNP: rs1555458413

Total submissions: 8

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: http://pkdb.mayo.edu/ 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	RCV001288337	SCV001475358	uncertain significance	not provided	2019-11-06	criteria provided, single submitter	clinical testing
(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)	RCV000757623	SCV002558715	pathogenic	Polycystic kidney disease, adult type	2022-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001288337	SCV002578805	uncertain significance	not provided	2024-02-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 33532864, 17574468, 23431072, 25333066, 22508176, 30816285, Liu2023[preprint], 33454723, 33639313, 36833371, DelAguilaGarcia2023[preprint])
PreventionGenetics, part of Exact Sciences	RCV003942616	SCV004758613	pathogenic	PKD1-related disorder	2024-01-05	criteria provided, single submitter	clinical testing	The PKD1 c.1831C>T variant is predicted to result in the amino acid substitution p.Arg611Trp. This variant has been widely reported in presumably unrelated individuals with autosomal dominant polycystic kidney disease (ADPKD) (see for example, Benson et al. 2021. PubMed ID: 33454723, Suppl. Table 3; Trujillano et al. 2014. PubMed ID: 25333066; Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Audrézet et al. 2012. PubMed ID: 22508176; http://pkdb.mayo.edu/). In addition, at PreventionGenetics, we have found this variant in presumably unrelated individuals tested for polycystic kidney disease. Of note, a different substitution at the same codon, defined as c.1832G>C (p.Arg611Pro), has also been reported in an individual with ADPKD (Mantovani et al. 2020. PubMed ID: 32457805, Supplementary Table 3). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
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.