rs1555454411

Variant names:

• chr16-2108680-G-A
• rs1555454411
• NM_001009944.3:c.6487C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.6487C>T​(p.Arg2163*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKD1 NM_001009944.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 2.88
• Publications: 4 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2108680-G-A is Pathogenic according to our data. Variant chr16-2108680-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 433972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.6487C>T	p.Arg2163*	stop_gained	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.6487C>T	p.Arg2163*	stop_gained	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415434 Hom.: 0 Cov.: 34 AF XY: 0.00000286 AC XY: 2 AN XY: 700218

African (AFR) AF: 0.00 AC: 0 AN: 32424

American (AMR) AF: 0.00 AC: 0 AN: 39068

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 37090

South Asian (SAS) AF: 0.00 AC: 0 AN: 80952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089280

Other (OTH) AF: 0.00 AC: 0 AN: 58480

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:5

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 06, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.6487C>T (p.Arg2163X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 181246 control chromosomes. c.6487C>T has been observed in individual(s) affected with Polycystic Kidney Disease 1 and segregation was established (example: Rossetti_2001). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 11115377). ClinVar contains an entry for this variant (Variation ID: 433972). Based on the evidence outlined above, the variant was classified as pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PP4+PS4_Supporting -

not provided Pathogenic:5

Jul 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant polycystic kidney disease Pathogenic:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Oct 03, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not specified Pathogenic:1

Feb 22, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jul 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Renal cyst Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.9
Vest4		0.90
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555454411; hg19: chr16-2158681;