Submissions for variant NM_001009944.3(PKD1):c.6487C>T (p.Arg2163Ter)

dbSNP: rs1555454411

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508539	SCV000604714	pathogenic	not specified	2017-02-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000681684	SCV000843155	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526541	SCV001736965	pathogenic	Renal cyst		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289687	SCV002580259	pathogenic	Polycystic kidney disease, adult type	2021-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000681684	SCV002757571	pathogenic	not provided	2022-07-29	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: 30586318, 25525159, 11967008, 11115377, 31317121, 30816285, 22508176, 19515475, 31488014, 33168999)
Fulgent Genetics, Fulgent Genetics	RCV002289687	SCV002814346	pathogenic	Polycystic kidney disease, adult type	2024-05-24	criteria provided, single submitter	clinical testing
3billion	RCV002289687	SCV003841381	pathogenic	Polycystic kidney disease, adult type	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000433972 / PMID: 11115377). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000681684	SCV005197156	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002289687	SCV005415871	pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PP4+PS4_Supporting
Ambry Genetics	RCV004955548	SCV005475086	pathogenic	Inborn genetic diseases	2024-07-09	criteria provided, single submitter	clinical testing	The c.6487C>T (p.R2163*) alteration, located in exon 15 (coding exon 15) of the PKD1 gene, consists of a C to T substitution at nucleotide position 6487. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2163. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals who met clinical criteria for autosomal dominant polycystic kidney disease (Audrézet, 2012; Al-Muhanna, 2019; Ali, 2023). Based on the available evidence, this alteration is classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000500237	SCV005900484	pathogenic	Autosomal dominant polycystic kidney disease	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change in PKD1 is a nonsense variant predicted to create a premature stop codon, p.(Arg2163*), in biologically relevant exon 15/46 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 25491204, 24694054, 29529603). Loss-of-function variants are a well-established cause of disease in exon 15 (ClinVar). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.00009% (1/1,157,320 alleles) in the European (non-Finnish) population, consistent with dominant disease. This variant has been reported in at least four unrelated probands with a clinical diagnosis of autosomal dominant polycystic kidney disease (PMID: 11115377, 22508176). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting, PM5_Supporting.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500237	SCV000592791	pathogenic	Autosomal dominant polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg2163X variant was identified in 4 of 1662 proband chromosomes (frequency: 0.002) from British and French individuals or families with ADPKD, segregating with the disease (Rossetti 2001, Audrézet 2012). The variant was identified in ADPKD Mutation Database with classification definitely pathogenic; and was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database (classification), PKD1-LOVD, and PKD1-LOVD 3.0, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, or the Exome Aggregation Consortium database (March 14, 2016). The p.Arg2163X variant leads to a premature stop codon at position 2163, 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	RCV000681684	SCV000809131	pathogenic	not provided	2018-09-16	no assertion criteria provided	research