Submissions for variant NM_001009944.3(PKD1):c.12031C>T (p.Gln4011Ter)

dbSNP: rs1555444985

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517296	SCV000614478	pathogenic	not provided	2016-10-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763369	SCV000894065	pathogenic	Polycystic kidney disease, adult type	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000517296	SCV003761938	pathogenic	not provided	2022-07-26	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: 25525159, 12220456, 9521593, 30650191, 33639313, 10729710, 10923038, 22508176, 35783601, 34032358, 25333066, 22383692)
Neuberg Centre For Genomic Medicine, NCGM	RCV000763369	SCV004171894	pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763369	SCV005416123	pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS2_Supporting+PS4_Supporting+PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292449	SCV001480971	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Gln4011* variant was identified in 6 of 2598 proband chromosomes (frequency: 0.002) from individuals or families with autosomal dominant polycystic kidney disease and was not identified in 518 control chromosomes from healthy individuals (Hwang 2016, Rossetti 2012, Eo 2002, Bogdanova 2000, Audrézet 2012, Daniells 1998, Kim 2000, Stekrova 2009). The variant was also identified in ClinVar (classified as pathogenic by Athena Diagnostics and Fulgent Genetics) and in the ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in LOVD 3.0 or the PKD1-LOVD databases. It was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Gln4011* variant leads to a premature stop codon at position 4011, 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.