16-2114489-A-G

Variant names:

• chr16-2114489-A-G
• rs199476100
• NM_001009944.3:c.2534T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_001009944.3(PKD1):​c.2534T>C​(p.Leu845Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,444,302 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 8.09
• Publications: 14 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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001009944.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 16-2114489-A-G is Pathogenic according to our data. Variant chr16-2114489-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.2534T>C	p.Leu845Ser	missense	Exon 11 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.2534T>C	p.Leu845Ser	missense	Exon 11 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.2534T>C	p.Leu845Ser	missense	Exon 11 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.2534T>C	p.Leu845Ser	missense	Exon 11 of 46	ENSP00000399501.1
	PKD1	ENST00000568591.5	TSL:2	n.*862T>C		non_coding_transcript_exon	Exon 7 of 12	ENSP00000457162.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 230128 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000851

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1444302 Hom.: 0 Cov.: 34 AF XY: 0.00000417 AC XY: 3 AN XY: 719042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.0000258 AC: 1 AN: 38790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111432

Other (OTH) AF: 0.00 AC: 0 AN: 60044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000292528), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:9

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008206). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26139440). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10364515, 15772804, 22383692, 26139440). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15772804, 22383692). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 02, 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.2534T>C (p.Leu845Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4.3e-06 in 230128 control chromosomes (gnomAD). c.2534T>C has been observed in multiple individuals affected with Polycystic Kidney Disease 1 (e.g., Thomas_1999, Kim_2019, Benson_2021, Domingo-Gallego_2022, Yan_2022, Nigro_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10364515, 26632257, 31740684, 33454723, 33532864, 36186434, 37372416). ClinVar contains an entry for this variant (Variation ID: 8206). 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

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Jul 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 27, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 7 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from Leu to Ser; This variant is heterozygous; 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); Variant is not located in an established domain, motif, hotspot or informative constraint region; Missense variant with inconclusive in silico prediction and uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900); Inheritance information for this variant is not currently available in this individual.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 05, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS1, PP3, PP4

not provided Pathogenic:5

Nov 20, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 15, 2024

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PKD1 gene demonstrated a sequence change, c.2534T>C, in exon 11 that results in an amino acid change, p.Leu845Ser. The p.Leu845Ser change affects a moderately conserved amino acid residue located in a domain of the PKD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu845Ser substitution. This amino acid change has been described in the literature in several individuals with autosomal dominant polycystic kidney disease (ADPKD) (PMID: 10364515, 33454723, 31740684, 26632257, 30816285, 15772804, 26139440). This sequence change has been described in the gnomAD database with a frequency of 0.0005% in the European subpopulation (dbSNP rs199476100). Collectively, this evidence indicates that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively.

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10854095, 22508176, 10364515, 25266109, 15772804, 23300259, 22383692, 26632257, 31740684, 30816285, 33454723, 35783601, 33532864, 37909612, Durkie2023[paper], 38224954, 38541974, 36186434, 26139440)

Polycystic kidney disease Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Leu845Ser variant was identified in 4 of 346 proband chromosomes (frequency: 0.012) from individuals or families of Chinese and Finnish ethnicity with ADPKD and was not identified in 420 control chromosomes from healthy individuals (Audrezet 2015, Liu 2015, Peltola 2005, Thomas 1999). Thomas et al (1999) identified the p.Leu845Ser variant in one affected individual and was not identified in the patient’s unaffected daughter. The variant was also identified in dbSNP (ID: rs199476100) as “With Pathogenic allele”, ClinVar database as pathogenic by OMIM and in ADPKD Mutation Database as highly likely pathogenic. The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases nor was it identified in the 1000 Genomes and the NHLBI GO Exome Sequencing Projects. The variant was identified in control databases in 1 of 226770 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Leu845Ser residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu845Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant predicts a change from a neutral and hydrophobic Leu to a polar Ser at position 845, six residues N-terminal to the start of PKD domain 2 (Thomas 1999). 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 variant is located within the Polycystin cation channel functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

PKD1-related disorder Pathogenic:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.2534T>C variant is predicted to result in the amino acid substitution p.Leu845Ser. This variant has been repeatedly reported in unrelated patients with autosomal dominant polycystic kidney disease (ADPKD) and it was widely documented as a “highly likely pathogenic” variant (Thomas et al. 1999. PubMed ID: 10364515; Liu et al. 2015. PubMed ID: 26632257; Peltola et al. 2005. PubMed ID: 15772804; http://pkdb.mayo.edu). This variant is reported in 0.0085% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Polycystic kidney disease 3 with or without polycystic liver disease Pathogenic:1

Mar 28, 2018

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.70		Gain of disorder (P = 0.0106)
MVP		0.98
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.91
Mutation Taster		=9/91	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: rs199476100; hg19: chr16-2164490;