Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV001251474 | SCV001427196 | pathogenic | Polycystic kidney disease, adult type | 2019-03-22 | criteria provided, single submitter | clinical testing | A heterozygous canonical splice-site variant, NM_001009944.2(PKD1):c.12444+1G>A, has been identified in Intron 45 of 45 of the PKD1 gene. The nucleotide at this position has very high conservation (Phylop UCSC). This nucleotide substitution is predicted to cause aberrant splicing of the last exon in the PKD1 gene (Human splicing Finder, NetGene2, Fruit fly). This variant is predicted to result in loss of protein function through truncation (RT-PCR confirms it affects splicing and causes p.(Phe4149Metfs*8) (Yu, C. et al (2014)), which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic and segregated with disease in one family with autosomal dominant polycystic kidney disease (Yu, C. et al (2014)). Other frameshift variants in the same region have also been shown to cause polycystic kidney disease (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. |
| Clinical Genetics Laboratory, |
RCV004697092 | SCV005197149 | pathogenic | not provided | 2024-01-12 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics, |
RCV005250166 | SCV005900290 | pathogenic | Autosomal dominant polycystic kidney disease | 2024-12-06 | criteria provided, single submitter | clinical testing | This sequence change in PKD1 occurs within the canonical splice acceptor site of intron 45. It is observed to cause cryptic donor site activation in RNA assays, resulting in an in-frame deletion (removes amino acids 4149-4304) that is expected to escape nonsense-mediated decay and remove <10% of the protein including the coiled coil domain which is a critical functional domain for PKD1 (PMID: 24575920, 9192675, 25574838). This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least two unrelated families with autosomal dominant polycystic kidney disease and segregates with disease in multiple affected individuals in one family (PMID: 24575920, 32939031). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Moderate, PS4_Moderate, PM2_Supporting |
| Department of Pathology and Laboratory Medicine, |
RCV001292153 | SCV001480730 | pathogenic | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKD1 c.12444+1G>A variant not identified in the dbSNP, ClinVar, ADPKD Mutation Database, or PKD1-LOVD databases. 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 variant was identified in the literature as pathogenic (Abdelwahed_2018_29860066, Yu_2014_24575920). In addition, functional studies by RT-PCR using primers located in exon-exon junctional region of the cDNA found that c.12444 + 1G>A definitely destroyed the native splice site and created a novel donor site with truncating effect (Yu_2014_24575920). It was also reported the variant was found to segregate with disease in three family members (Yu_2014_24575920). The c.12444+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence; 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |