ClinVar Genomic variation as it relates to human health

The PKD1 c.4306C>T; p.Arg1436Ter variant is reported in the literature in several individuals and families affected with autosomal dominant polycystic kidney disease (Garcia-Gonzalez 2007, Ranjzad 2018, Xu 2018). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Garcia-Gonzalez MA et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7. Ranjzad F et al. Identification of Three Novel Frameshift Mutations in the PKD1 Gene in Iranian Families with Autosomal Dominant Polycystic Kidney Disease Using Efficient Targeted Next-Generation Sequencing. Kidney Blood Press Res. 2018;43(2):471-478. Xu D et al. Novel Mutations in the PKD1 and PKD2 Genes of Chinese Patients with Autosomal Dominant Polycystic Kidney Disease. Kidney Blood Press Res. 2018;43(2):297-309.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29590654, 23300259, 29633482, 27535533, 31740684, 29529603, 17574468, 28578020, 22367170, 25525159)

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 15 of 46). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable NMD causing variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Garcia-Gonzalez, M. et al. (2007), Liu, Y. et al. (2015), Liu, B. et al. (2015), Kinoshita, M. et al. (2016), Wang, T. et al. (2019)). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families.

PVS1, PS4, PM2

The PKD1 p.Arg1436* variant was identified in 7 of 2502 proband chromosomes (frequency: 0.003) from individuals or families with autosomal dominant polycystic kidney disease (ADPKD) and was not identified in 280 control chromosomes from healthy individuals (Audrezet 2012, Garcia-Gonzalez 2007, Hwang 2016, Kinoshita 2016, Liu 2015, Liu 2015, Ranjzad 2018). The variant was also identified in ClinVar (as pathogenic by Columbia University), LOVD 3.0 (as pathogenic), and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP 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). The p.Arg1436* variant leads to a premature stop codon at position 1436 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

The PKD1 c.4306C>T variant is predicted to result in premature protein termination (p.Arg1436*). This variant has been reported to be pathogenic for autosomal dominant polycystic kidney disease (ADPKD) (see for example at Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Ranjzad et al. 2018. PubMed ID: 29590654; Groopman et al. 2019. PubMed ID: 30586318, Table S7). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PKD1 are expected to be pathogenic. This variant is interpreted as pathogenic.