rs148812376

Variant names:

• chr16-2099955-G-A
• rs148812376
• NM_001009944.3:c.9829C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2099955-G-A
• chr16-2099955-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3277P) has been classified as Uncertain significance.

• 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:9 U:1 B:1 O:1
• Conservation: PhyloP100: 7.38
• Publications: 69 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 192320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9829C>T	p.Arg3277Cys	missense_variant	Exon 29 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9829C>T	p.Arg3277Cys	missense_variant	Exon 29 of 46	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.000167 AC: 29 AN: 174022 AF XY: 0.000161

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 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

African (AFR) AF: 0.0000621 AC: 2 AN: 32192

American (AMR) AF: 0.0000539 AC: 2 AN: 37132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 37000

South Asian (SAS) AF: 0.00 AC: 0 AN: 80750

European-Finnish (FIN) AF: 0.000164 AC: 8 AN: 48906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.000410 AC: 446 AN: 1087412

Other (OTH) AF: 0.000188 AC: 11 AN: 58430

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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:9 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:6 Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 VUS, however, it is commonly described as a hypomorphic pathogenic or likely pathogenic allele. It has been reported in multiple homozygous and compound heterozygous individuals with polycystic kidney disease, but also in mildly affected heterozygous individuals with renal cysts (ClinVar, GeneReviews, 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 -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Hypomorphic allele -

May 23, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Benign:1

Aug 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 23064367); 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, 24907393, 29463793, 31589614, 35325889, 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, 19165178, 23431072, 23064367, 30476936, 20301424, 35372954, 35368817, 40114603, 27499327, 39145639, 39026710, 38385746, 37953472, 38854144, 31808745, 28194574, 34169210, 40554762, 36564419, 40237039, 40300563, 31042058, 36422996, 40061354, 33802342) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely benign

Review Status: flagged submission

Collection Method: research

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease Pathogenic:1

Jun 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.9829C>T (p.Arg3277Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00017 in 174022 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, allowing no conclusion about variant significance. c.9829C>T has been observed as a hypomorphic variant in multiple individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease (e.g., Rossetti_2009). In one family it was found in an in-utero onset individual who was compound heterozygous with a nonsense variant, while in another family it was found in 2 homoyzgous cases with typical end stage renal disease, and several heterozygous carriers had mild disease. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function using a mouse knockin model (Hopp_2012). The variant in combination with a null allele resulted in rapidly progressive disease, while the mice homozygous for the variant developed gradual cystogenesis. The variant also resulted in folding/trafficking defects and length defects in collecting duct primary cilia. The following publications have been ascertained in the context of this evaluation (PMID: 23064367, 19165178). ClinVar contains an entry for this variant (Variation ID: 192320). Based on the evidence outlined above, the variant was classified as pathogenic for Polycystic Kidney Disease 1 and PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, with evidence of a hypomorphic effect. -

Autosomal dominant polycystic kidney disease Uncertain:1

Jan 01, 2019

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

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

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
PhyloP100		7.4
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
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs148812376; hg19: chr16-2149956;