16-2114843-A-G
Variant summary
Our verdict is Pathogenic. The variant received 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
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant polycystic kidney diseaseInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- polycystic kidney disease 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- autosomal recessive polycystic kidney diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Caroli diseaseInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
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.2180T>C | p.Leu727Pro | missense | Exon 11 of 46 | NP_001009944.3 | ||
| PKD1 | NM_000296.4 | c.2180T>C | p.Leu727Pro | 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.2180T>C | p.Leu727Pro | missense | Exon 11 of 46 | ENSP00000262304.4 | ||
| PKD1 | ENST00000423118.5 | TSL:1 | c.2180T>C | p.Leu727Pro | missense | Exon 11 of 46 | ENSP00000399501.1 | ||
| PKD1 | ENST00000568591.5 | TSL:2 | n.*508T>C | non_coding_transcript_exon | Exon 7 of 12 | ENSP00000457162.1 |
Frequencies
GnomAD3 genomes
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 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:9
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, 40069205, 36186434, 35325889, 33315352, 37372416, 38527221, 38481516, 26139440, 29801666, 32398770, 39928271)
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.
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.
PM2, PM5, PS4
PKD1: PS4, PM2, PM5, PP4
Polycystic kidney disease, adult type Pathogenic:8Uncertain:1
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
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.;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.
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.
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.42; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000562302). A different missense change at the same codon (p.Leu727Gln) has been reported to be associated with PKD1 related disorder (PMID: 29801666). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
PM2, PP3, PP4, PP5
The c.2180T>C (p.Leu727Pro) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with polycystic kidney disease-1 (PMID: 17582161, 23431072, 24374109, 29038287, 30333007, 31027891, 33315352, 33454723, 33437033, 36186434). Different amino acid changes at the same residue (p.Leu727Arg; p.Leu727Gln) have been previously reported in individuals with polycystic kidney disease-1 (PMID: 21115670, 36082560, 29801666). The c.2180T>C (p.Leu727Pro) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.2180T>C (p.Leu727Pro) is classified as Likely Pathogenic.
Autosomal dominant polycystic kidney disease Pathogenic:3
A female patient with clinical manifestations of renal cyst found the mutation site NM_001009944.3(PKD1):c.2180T>C through whole exon detection, and this mutation has been reported in the literature (PMID: 17582161). According to ACMG guidelines, the mutation conforms to PS4 (The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls),PM2 (Absent from controls in Exome Sequencing Project, 1000 Genomes or ExAC),and PP3 (Multiple lines of computational evidence support a deleterious effect on the gene or gene product), so the mutation point is considered as suspicious pathogenicity.
This sequence change in PKD1 is predicted to replace leucine with proline at codon 727, p.(Leu727Pro). The leucine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the extracellular region. There is a moderate physicochemical difference between leucine and proline. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple individuals with a clinical diagnosis of autosomal dominant polycystic kidney disease (ADPKD) and segregates with disease in at least two unrelated families (PMID: 30333007, 26139440, 22508176, 22383692, 21115670, 23431072, ADPKD Database). Computational evidence is uninformative for the missense substitution (REVEL = 0.422). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM2_Supporting, PP1_Moderate
Polycystic kidney disease Pathogenic:1
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.
Polycystic kidney disease 3 with or without polycystic liver disease Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at