rs148812376

chr16-2099955-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM1 PP3_Strong PP5_Very_Strong BS2

The NM_001009944.3(PKD1):c.9829C>T(p.Arg3277Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,563,456 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 B:1 O:1
• Conservation: PhyloP100: 7.38

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 181) in uniprot entity PKD1_HUMAN there are 61 pathogenic changes around while only 23 benign (73%) in NM_001009944.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 16-2099955-G-A is Pathogenic according to our data. Variant chr16-2099955-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2099955-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.9829C>T	p.Arg3277Cys	missense_variant	29/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.9829C>T	p.Arg3277Cys	missense_variant	29/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 29 AN: 174022 Hom.: 0 AF XY: 0.000161 AC XY: 15 AN XY: 92972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000114

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000422

GnomAD4 exome AF: 0.000332 AC: 469 AN: 1411198 Hom.: 0 Cov.: 32 AF XY: 0.000325 AC XY: 227 AN XY: 697720

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.0000539

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000164

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000188

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000373 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000128 AC: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (46 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as a likely hypomorphic allele, and has been reported in homozygous and compound heterozygous patients with polycystic kidney disease, but also in mildly affected heterozygous patients with renal cysts (ClinVar, PKD Mutation Database). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function through defective PC-1 cleavage, protein folding and trafficking (PMID: 23064367). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 09, 2021	The PKD1 c.9829C>T (p.Arg3277Cys) variant is described as a hypomorphic allele proposed to modulate renal cyst development, which when detected in a homozygous or compound heterozygous state may result in a severe PKD phenotype but in a heterozygote state may cause a few cysts or no evidence of disease (Rossetti et al. 2009; Harris and Torres 2018). Across a selection of the available literature, the p.Arg3277Cys variant, a missense variant, has been identified in at least 17 individuals with polycystic kidney disease (PKD), including four in a homozygous state and six in a compound heterozygous state most of whom had severe, early-onset PKD (Rossetti et al. 2009; Vujic et al. 2010; Audrezet et al. 2016; Mantovani et al. 2020; Durkie et al. 2021). In a four generation consanguineous family in which the p.Arg3277Cys variant segregated with disease, the variant was also found in six individuals in a heterozygous state including five individuals presenting with a mild phenotype ranging from one to five simple cysts in adulthood and in one individual with no evidence of disease (Rossetti et al. 2009). Durkie et al. (2021) describe an additional individual heterozygous for the p.Arg3277Cys variant presenting with a severe, prenatal-onset phenotype and death shortly after birth, however a second, unidentified variant is suspected due to his unaffected father carrying the p.Arg3277Cys variant and his affected mother not having an identified variant. The p.Arg3277Cys variant was also found in at least five unaffected parents of an affected individual (Audrezet et al. 2016: Vujic et al. 2010; Durkie et al. 2021), although ages of the parents were not consistently specified. Control data are unavailable for this variant, which is reported at a frequency of 0.000453 in the European (non-Finnish) population of the Genome Aggregation Database v2.1.1. This allele frequency is high but may be consistent with reduced penetrance/hypomorphic allele. A knock-in mouse model found that heterozygous mice did not present with PKD but did find that homozygous, and compound heterozygous mice respectively demonstrated progressively more severe phenotypes consistent with human PKD patients, indicating the p.Arg3277Cys variant is dosage dependent and a hypomorphic modifier of the PKD phenotype (Hopp et al. 2012). Based on the collective evidence, the p.Arg3277Cys variant is classified as pathogenic (hypomorphic) for autosomal dominant polycystic kidney disease, generally associated with mild or no disease when detected in a heterozygous state and with a more severe, earlier-onset phenotype when detected in trans with a second variant. -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg3277Cys variant in PKD1 was identified by our study in one individual with polycystic kidney disease and their unaffected parent. This variant has been seen in 0.04351% (36/82736) of European (non-Finnish) chromosomes. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg3277Cys variant in PKD1 has been reported in ten individuals in one cosanguineous family with polycystic kidney disease and segregated with disease in eight affected relatives with varying expressivity. The disease status of the remaining two relatives was unknown (PMID: 19165178). This variant was also reported in the compound heterozygous state (with a pathogenic variant in one case) in two unrelated individuals with polycystic kidney disease (PMID: 19165178, 26139440). The presence of this variant in combination with a reported pathogenic variant and in an individual with polycystic kidney disease increases the likelihood that the p.Arg3277Cys variant is pathogenic. Animal models in mice have shown that this variant in the homozygous and compound heterozygous state with a null variant does cause a phenotype matching polycystic kidney disease (PMID: 23064367). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PP1_Moderate, PM3, PS3 (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	Hypomorphic allele -

not provided Pathogenic:1 Benign:1

Likely benign, flagged submission	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	A knock-in mouse model demonstrated mice that were heterozygous for the R3277C variant had no clinical features, homozygous mice developed gradual cystogenesis, and mice that were compound heterozygous for the R3277C variant and a null allele had rapidly progressive disease (Hopp et al., 2012); 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: 30249452, 32457805, 28903946, 19165178, 23064367, 24907393, 29463793, 23431072, 31589614, 34953771, 34662459, 33639313, 34290017, 34806449, 35037466, 34671066, 33705824, 26139440, 33168999, 33437033, DurkieM2023[Article], 37345660, 37372410, ChenJM2023[Preprint], 37519231, 37231942, 35896062, 37418622, 20558538, 32939031, 35358475, 37543885) -

Autosomal dominant polycystic kidney disease Uncertain:1

Uncertain significance, flagged submission

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.98
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.88
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148812376; hg19: chr16-2149956;