chr16-2093916-GACAGCC-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM4PP5_Very_Strong
The NM_001009944.3(PKD1):c.10710_10715delGGCTGT(p.Ala3571_Val3572del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000699 in 1,430,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001009944.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.10710_10715delGGCTGT | p.Ala3571_Val3572del | disruptive_inframe_deletion | Exon 36 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000699 AC: 10AN: 1430312Hom.: 0 AF XY: 0.00000845 AC XY: 6AN XY: 709984
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:2
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The PKD1 c.10710_10715del; p.Ala3571_Val3572del variant (rs777460677) has been described in the literature in association with autosomal dominant polycystic kidney disease (ADPKD; Alberer 2010, Canaud 2010, He 2018). It is reported in ClinVar (Variation ID: 434001), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes 2 residues (alanine and valine), leaving the rest of the protein in-frame. Based on available information, this variant is considered likely pathogenic. REFERENCES Alberer M et al. Reduced methotrexate clearance and renal impairment in a boy with osteosarcoma and earlier undetected autosomal dominant polycystic kidney disease (ADPKD). J Pediatr Hematol Oncol. 2010 Nov;32(8):e314-6. Canaud G et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am J Transplant. 2010 Jul;10(7):1701-6. He W et al. Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction. BMC Med Genet. 2018 Oct 17;19(1):186. -
not provided Pathogenic:2
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In-frame deletion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20642692, 20921908, 30333007, 37509056) -
Autosomal dominant polycystic kidney disease Pathogenic:1
The p.Ala3571_Val3572del variant was identified by Cannaud (2010) in a kidney donor, whose kidneys were transplanted in two recipients. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a novel hypomorphic mutation in PKD1 (10710_10715del6) as the only likely mutation. This deletion is located in the fourth transmembrane (TM) region of polycystin-1 and is predicted to change the site of the TM domain. The p.Ala3571_Val3572del variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC version 0.3 released January 13, 2015), COSMIC, MutDB, the ClinVar, Clinvitae, GeneInsight COGR through the Canadian Open Genetics Repository (http://opengenetics.ca/) and in LOVD PKD1 and LOVD3.0 PKD1 Databases. The variant was identified in the Mayo Clinic PKD1 database and was classified as Likely Pathogenic. This variant is an in-frame deletion resulting in the removal of Ala residue at codon 3571 and Val residue at codon 3572 resulting in loss a critical domain region and potentially loss of function. This type of variant is expected to cause Autosomal Dominant Polycystic Kidney Disease, consistent with the clinical diagnosis in this individual. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at