16-2114843-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001009944.3(PKD1):c.2180T>C(p.Leu727Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L727R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000023 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PKD1
NM_001009944.3 missense
NM_001009944.3 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 5.42
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927
PP5
Variant 16-2114843-A-G is Pathogenic according to our data. Variant chr16-2114843-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114843-A-G is described in Lovd as [Likely_pathogenic]. Variant chr16-2114843-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKD1 | NM_001009944.3 | c.2180T>C | p.Leu727Pro | missense_variant | 11/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000231 AC: 3AN: 1300448Hom.: 0 Cov.: 25 AF XY: 0.00000465 AC XY: 3AN XY: 645642
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
3
AN:
1300448
Hom.:
Cov.:
25
AF XY:
AC XY:
3
AN XY:
645642
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 03, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 22383692, 21115670, 27835667, 22508176, 24374109). Computational tools predict that this variant is damaging. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 21, 2018 | The PKD1 c.2180T>C; p.Leu727Pro variant (rs1616940) is reported in the literature in 27 unrelated patients with autosomal dominant polycystic kidney disease (Audrezet 2012, Carrera 2016, Cornec-Le Gall 2013, Hoefele 2011, Rossetti 2007, Rosetti 2012, Tan 2014) and is also listed on gene-specific databases (Mayo ADPKD Mutation Database) . This variant is absent from the general population with an average of 126647 alleles reported for this genomic region (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 727 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging. Based on the above information, this variant is considered likely pathogenic. References: Mayo ADPKD Mutation Database: http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?GENE=PKD1&apkd_mode=PROD Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012 Aug;33(8):1239-50. Carrera P et al. Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sci Rep. 2016; 6: 30850. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13. Hoefele J et al. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2011 Jul;26(7):2181-8. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. Tan A et al. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J Mol Diagn. 2014 Mar;16(2):216-28. - |
| Likely pathogenic, flagged submission | clinical testing | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2024 | 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: 26661679, 24374109, 23431072, 22090377, 17582161, 30333007, 25333066, 25646624, 27499327, 22508176, 21115670, 22383692, 29038287, 30816285, 33454723, 33437033, 33532864, 27835667, 30586318, 31027891, 38689396, 36699011, 37372410, Gao2024[CaseReport], 36186434, 35325889, 33315352) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 02, 2023 | PM2, PM5, PS4 - |
Polycystic kidney disease, adult type Pathogenic:6Uncertain:1
| Uncertain significance, flagged submission | research | Cavalleri Lab, Royal College of Surgeons in Ireland | Feb 05, 2020 | PM2, PP3, PP4, PP5 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4+PP1+PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 28, 2023 | The inherited c.2180T>C p.(Leu727Pro) variant in PKD1 has been reported in the literature in multiple individuals with polycystic kidney disease 1 [PMID: 23431072, 24374109, 29038287, 30333007, 30586318, 31027891, 30816285, 33315352, 33532864, 33437033] and is listed in the Mayo Clinic Polycystic Kidney Disease variant database as Likely Pathogenic [https://pkdb.mayo.edu/variants]. The c.2180T>C variant has been deposited in ClinVar with conflicting interpretations of pathogenicity by multiple submitters, including six Pathogenic and seven Likely Pathogenic entries [ClinVar ID: 562302], and is absent from the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. In silico predictions do not support or refute a damaging effect for p.(Leu727Pro) [CADD score = 24.6, REVEL score = 0.422]. Two other missense variants, p.(Leu727Gln) and p.(Leu727Arg), have also been listed as likely pathogenic in the Mayo Clinic Polycystic Kidney Disease variant database. Based on available evidence, the inherited heterozygous c.2180T>C p.(Leu727Pro) variant identified in PKD1 is classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic in ClinVar and the Autosomal Dominant Polycystic Kidney Disease (ADPKD) Database (PKDB). It has been reported in multiple individuals with ADPKD in the literature (PMID: 22508176; 24374109). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Polycystic kidney disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Leu727Pro variant was identified in 19 of 3592 proband chromosomes (frequency: 0.005) from German, French, North American, Spanish, Italian and Japanese individuals or families with ADPKD, and was not identified in 480 control chromosomes from healthy individuals (Hoefele 2011, Audrézet 2012, Rossetti 2012, Hwang 2016, Trujillano 2014, Carrera 2016, Kinoshita 2016). The variant was also identified in dbSNP (ID: rs1616940), ADPKD Mutation Database (classified as Highly Likely Pathogenic), PKD1-LOVD 3.0 (classification by in silico as affecting protein function) and Clinvitae (1X). The variant was not identified in NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (March 14, 2016), the Genome Aggregation Consortium, ClinVar, COGR, MutDB and PKD1-LOVD. The p.Leu727 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses programs (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant is located within a functional domain, the polycystin cation channel, increasing the likelihood that it could have clinical significance. This variant was identified in 2 individuals by our laboratory one young individual with cystic kidney disease and another under the age of 35 with bilateral multicystic kidney disease, hepatic cysts and a family history of ADPKD, increasing the likelihood it may have clinical significance. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Autosomal dominant polycystic kidney disease Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Polycystic kidney disease 3 with or without polycystic liver disease Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Mar 28, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of stability (P = 0.0264);Loss of stability (P = 0.0264);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at