Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000778797 | SCV000915168 | uncertain significance | Autosomal recessive polycystic kidney disease | 2018-10-24 | criteria provided, single submitter | clinical testing | The PKHD1 c.12142C>T (p.Gln4048Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant is however, located in last exon of the PKHD1 gene and may escape nonsense-mediated decay. A literature search was performed for the gene, cDNA change, and amino acid change. Based on this search no publications were found reporting the p.Gln4048Ter variant in association with polycystic kidney disease, autosomal recessive, however the p.Gln4048Ter variant was reported in one study in a 64 year old female with polycystic liver disease, in a heterozygous state (Besse et al. 2017). The p.Gln4048Ter variant is reported at a frequency of 0.00084 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence and the potential impact of stop-gained variants, the p.Gln4048Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for an autosomal recessive form of polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Victorian Clinical Genetics Services, |
RCV002272350 | SCV002557722 | uncertain significance | Polycystic kidney disease 4 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive 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) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (96 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other downstream truncating variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Variants p.(Cys4054*) and p.(Ala4056Profs*29) are both classified as uncertain significance (ClinVar). 0809 - Previous evidence of pathogenicity for this variant is inconclusive. In ClinVar this variant has been reported as uncertain significance. It has also been published in a heterozygous 64-year-old female individual with dominantly inherited polycystic liver disease (PCLD), however the association of PKHD1 and PCLD is not established (PMID: 28375157). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Yale Center for Mendelian Genomics, |
RCV000845131 | SCV000987067 | likely pathogenic | Autosomal dominant polycystic liver disease | 2017-04-04 | no assertion criteria provided | literature only |