rs1555458413

Positions:

• chr16-2116010-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001009944.3(PKD1):​c.1831C>T​(p.Arg611Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 0.739

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2116009-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 16-2116010-G-A is Pathogenic according to our data. Variant chr16-2116010-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433949.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=3}. Variant chr16-2116010-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.1831C>T	p.Arg611Trp	missense_variant	9/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.1831C>T	p.Arg611Trp	missense_variant	9/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.1831C>T	p.Arg611Trp	missense_variant	9/46	1		A2
PKD1	ENST00000488185.2	c.472+1479C>T		intron_variant		5
PKD1	ENST00000568591.5	c.*159C>T		3_prime_UTR_variant, NMD_transcript_variant	5/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Feb 05, 2020	PM2, PP3, PP4, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2018	The PKD1 c.1831C>T; p.Arg611Trp variant is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Audrezet 2012, Cornec Le-Gall 2013, Garcia-Gonzalez 2007). This variant is reported as likely pathogenic in ClinVar (Variation ID: 433949) and the Mayo ADPKD variant database, and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 611 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on its occurrence in multiple individuals clinically diagnosed with autosomal dominant polycystic kidney disease, the p.Arg611Trp variant is considered to be likely pathogenic. References: Link to Mayo ADPKD variant database: http://pkdb.mayo.edu/ Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013; 24(6):1006-13. Garcia-Gonzalez M et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007; 92(1-2):160-7. -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)	Aug 03, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 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: 33532864, 17574468, 23431072, 25333066, 22508176, 30816285, Liu2023[preprint], 33454723, 33639313, 36833371, DelAguilaGarcia2023[preprint]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2019	- -

Polycystic kidney disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 .Arg611Trp variant was identified in 4 of 1564 proband chromosomes (frequency: 0.003) from individuals or families with Autosomal Dominant Polycystic Kidney Disease based on standard ultrasound criteria (Audrézet 2012, Garcia-Gonzalez 2007). The variant was also identified in the ADPKD Mutation Database (as “likely pathogenic”). The variant was not found in dbSNP, the Exome Aggregation Consortium database (March 14 2016), Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The p.Arg611 residue is conserved across mammals and other organisms, and computational analyses (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 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. 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The PKD1 c.1831C>T variant is predicted to result in the amino acid substitution p.Arg611Trp. This variant has been widely reported in presumably unrelated individuals with autosomal dominant polycystic kidney disease (ADPKD) (see for example, Benson et al. 2021. PubMed ID: 33454723, Suppl. Table 3; Trujillano et al. 2014. PubMed ID: 25333066; Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Audrézet et al. 2012. PubMed ID: 22508176; http://pkdb.mayo.edu/). In addition, at PreventionGenetics, we have found this variant in presumably unrelated individuals tested for polycystic kidney disease. Of note, a different substitution at the same codon, defined as c.1832G>C (p.Arg611Pro), has also been reported in an individual with ADPKD (Mantovani et al. 2020. PubMed ID: 32457805, Supplementary Table 3). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.75		Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);
MVP		0.97
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555458413; hg19: chr16-2166011;