Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001286232 | SCV001472765 | likely pathogenic | Polycystic kidney disease, adult type | 2019-11-21 | criteria provided, single submitter | clinical testing | The PKD1 c.12721C>T; p.Gln4241Ter variant is reported in the literature in at least one individual affected with autosomal dominant polycystic kidney disease (ADPKD) (Hoefele 2011, see link to ADPKD mutation database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the PKD1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Additionally, the carboxy-terminal portion of the protein is critical for protein function (Vandorpe 2001) and two downstream truncating variants (p.Gln4242Ter and p.Gln4247Ter) have been described in individuals with ADPKD (Mallawaarachchi 2016, Stekrova 2009). Based on available information, this variant is considered to be likely pathogenic. References: Link to ADPKD mutation database: https://pkdb.mayo.edu/cgi-bin/v2_desig_display.cgi?germ=Germline&gene=PKD1&designation=Q4241X&clinical=Definitely%20Pathogenic&score=&gene_mutation_id=1729&apkd_mode=PROD&username= Hoefele J et al. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2011 Jul;26(7):2181-8. Mallawaarachchi AC et al. Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur J Hum Genet. 2016 Nov;24(11):1584-1590. 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. Vandorpe DH et al. The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel. J Biol Chem. 2001 Feb 9;276(6):4093-101. |
| Victorian Clinical Genetics Services, |
RCV001286232 | SCV002557641 | pathogenic | Polycystic kidney disease, adult type | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (ADPKD) (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not predicted to truncate an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other truncating variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. At least two downstream truncating variants have previously been reported (ClinVar, PMID: 27165007). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in at least six individuals with ADPKD (MIM#173900) (ClinVar, LOVD, PMID: 21115670). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV001286232 | SCV002798474 | pathogenic | Polycystic kidney disease, adult type | 2022-01-26 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001292198 | SCV001480949 | pathogenic | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKD1 p.Gln4241* variant was not identified in the literature nor was it identified in the dbSNP, ClinVar and PKD1-LOVD databases. The variant was identified in LOVD 3.0 (observed 1x) and ADPKD Mutation Database (observed 1x). 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 c.12721C>T variant leads to a premature stop codon at position 4241 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 autosomal dominant polycystic kidney disease 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. |