ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.12010C>T (p.Gln4004Ter)

dbSNP: rs766551411
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000681726 SCV000885951 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing The PKD1 c.12010C>T; p.Gln4004Ter variant (rs766551411) has been reported in two families with autosomal dominant polycystic kidney disease, and segregating with affected individuals (Audrezet 2012). An immortalized cell line carrying the variant shows reduced PKD1 incorporation in the cellular membrane, and absence in the primary cilia (Herbert 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 434006), and is observed in the general population at a low overall frequency of 0.0004% (1/240348 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Herbert B et al. A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X) in polycystin-1. PLoS One. 2013; 8(1):e55191.
Blueprint Genetics RCV000681726 SCV000927280 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000681726 SCV001167685 pathogenic not provided 2022-03-04 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: 23383103, 25525159, 16456780, 22508176, 25333066, 29529603, 31740684, 30413633)
Fulgent Genetics, Fulgent Genetics RCV001536116 SCV001752832 pathogenic Polycystic kidney disease, adult type 2022-05-06 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001536116 SCV002768002 pathogenic Polycystic kidney disease, adult type 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been previously reported as pathogenic, and observed in many patients with polycystic kidney disease (PKD) (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and has been observed in patients with PKD (ClinVar, PMID: 29529603, pkdb.mayo.edu) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000504063 SCV000592859 pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Gln4004X variant was identified in 1 of 24 proband chromosomes from a small “discovery” cohort in a study developing NGS sequencing of ADPKD genes (Trjillano 2014). The variant was also identified in dbSNP (ID: rs766551411) and ADPKD Mutation Database (definitely pathogenic). The variant was not found in Clinvitae, COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, NHLBI GO, the Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln4004X variant leads to a premature stop codon at position 4004, 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.
Gharavi Laboratory, Columbia University RCV000681726 SCV000809179 pathogenic not provided 2018-09-16 no assertion criteria provided research

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