Submissions for variant NM_001009944.3(PKD1):c.3202C>T (p.Gln1068Ter)

dbSNP: rs2092538738

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249161	SCV001422363	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)	RCV002273845	SCV002558716	pathogenic	Polycystic kidney disease, adult type	2022-08-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002273845	SCV002815282	pathogenic	Polycystic kidney disease, adult type	2022-04-05	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002273845	SCV005416203	likely pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting
Molecular Genetics, Royal Melbourne Hospital	RCV005250164	SCV005900450	pathogenic	Autosomal dominant polycystic kidney disease	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change in PKD1 is a nonsense variant predicted to cause a premature stop codon, p.(Gln1068*), in biologically relevant exon 14/46 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 20301424). This variant is absent from the population database gnomAD v4.1. ClinVar contains an entry for this variant (Variation ID: 972875). This variant has been reported in at least three probands with polycystic kidney disease (PMID: 33437033, 37372416; ClinVar: SCV002558716.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PS4_Supporting, PVS1.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292117	SCV001480974	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Gln1068X variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, LOVD 3.0, and PKD1-LOVD databases. The variant was identified in ADPKD Mutation database 1X as definitely pathogenic. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Gln1068X variant leads to a premature stop codon at position 1068, 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.