chr16-2114843-A-C

Variant names:

• chr16-2114843-A-C
• rs1616940
• NM_001009944.3:c.2180T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001009944.3(PKD1):​c.2180T>G​(p.Leu727Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000769 in 1,300,450 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L727Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 5.42
• Publications: 11 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2114843-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586255.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 16-2114843-A-C is Pathogenic according to our data. Variant chr16-2114843-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 994718.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2180T>G	p.Leu727Arg	missense_variant	Exon 11 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2180T>G	p.Leu727Arg	missense_variant	Exon 11 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.69e-7 AC: 1 AN: 1300450 Hom.: 0 Cov.: 25 AF XY: 0.00000155 AC XY: 1 AN XY: 645642

African (AFR) AF: 0.00 AC: 0 AN: 29520

American (AMR) AF: 0.00 AC: 0 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24618

East Asian (EAS) AF: 0.00 AC: 0 AN: 35302

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3920

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1005506

Other (OTH) AF: 0.00 AC: 0 AN: 54880

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:2 Uncertain:1

Oct 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2024

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: 1 heterozygote(s), 0 homozygote(s)); This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS and as likely pathogenic by clinical laboratories in ClinVar and has been reported in the literature in an individual with ADPKD (PMID: 21115670); Other missense variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Leu727Pro) and p.(Leu727Gln), have been classified as likely pathogenic/pathogenic by clinical laboratories (pkdb.mayo.edu, ClinVar); p.(Leu727Gln) has also been classified as a VUS (ClinVar); Missense variant consistently predicted to be damaging by in silico tool or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from leucine to arginine; 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); No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; Variant is not located in an established domain, motif, hotspot or informative constraint region; 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.

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1-related disorder Pathogenic:1

Sep 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.2180T>G variant is predicted to result in the amino acid substitution p.Leu727Arg. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The p.Leu727 residue is highly conserved during evolution from frog to human. This variant has been reported in an individual with polycystic kidney disease (Hoefele et al. 2010. PubMed ID: 21115670). In addition, we have found this variant in the heterozygous state in three presumably unrelated patients tested for polycystic kidney disease at PreventionGenetics. Of note, different substitutions at this codon have been reported in individuals with polycystic kidney disease (Human Gene Mutation Database - HGMD; https://pkdb.mayo.edu/variants). This variant is interpreted as likely pathogenic.

not provided Uncertain:1

Jan 09, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		5.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.83
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.57
gMVP		0.93
Mutation Taster		=9/91	disease causing

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: rs1616940; hg19: chr16-2164844;