Submissions for variant NM_001009944.3(PKD1):c.7666C>T (p.Gln2556Ter)

dbSNP: rs1567184366

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756534	SCV000884369	pathogenic	Polycystic kidney disease, adult type	2020-03-04	criteria provided, single submitter	clinical testing	The PKD1 c.7666C>T; p.Gln2556Ter variant is reported in the literature in at least one patient with autosomal dominant polycystic kidney disease (ADPKD) (Garcia-Gonzalez 2007). The variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The p.Gln2556Ter variant induces a premature termination codon. An in vitro study showed that it resulted in a truncated protein in human cell lines derived from cyst of patients with ADPKD (Nauli 2006). Based on the above information, this variant is considered pathogenic. References: Garcia-Gonzalez 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. Nauli et al. Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol. 2006 Apr;17(4):1015-25.
GeneDx	RCV001849090	SCV002104320	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	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 (gnomAD); This variant is associated with the following publications: (PMID: 30215095, 16565258, 17574468, 17582161, 26453610, 28522688)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292279	SCV001480964	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Gln2556X variant was identified in 6 of 1008 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Garcia-Gonzalez 2007, Hwang 2016, Rossetti 2007). This variant was also identified in ADPKD Mutation Database (as definitely pathogenic). This variant was not identified in the following databases: dbSNP, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the Genome Aggregation database, COGR, ClinVar, Clinvitae, PKD1-LOVD, and PKD1-LOVD 3.0. In functional studies a cell line was derived from a cyst containing a germline p.Gln2556X variant that was determined to be causative of cyst formation (Nauli 2006). The p.Gln2556X variant leads to a premature stop codon at position 2556, 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.
PreventionGenetics, part of Exact Sciences	RCV004740442	SCV005347103	pathogenic	PKD1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The PKD1 c.7666C>T variant is predicted to result in premature protein termination (p.Gln2556*). This variant has been reported to be causative for autosomal dominant polycystic kidney disease (ADPKD) (Garcia-Gonzalez et al. 2007. PubMed ID: 17574468). We interpret this variant as pathogenic.