rs200391019

Variant names:

• chr6-52024940-G-A
• rs200391019
• NM_138694.4:c.4870C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52024940-G-A
• chr6-52024940-G-C
• chr6-52024940-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_138694.4(PKHD1):​c.4870C>T​(p.Arg1624Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,614,068 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. R1624Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34
• Conservation: PhyloP100: 4.82
• Publications: 44 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_138694.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 6-52024940-G-A is Pathogenic according to our data. Variant chr6-52024940-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188369.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
PKHD1	NM_138694.4	c.4870C>T	p.Arg1624Trp	missense_variant	Exon 32 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.4870C>T	p.Arg1624Trp	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.4870C>T	p.Arg1624Trp	missense_variant	Exon 32 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251416 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.000100 AC XY: 73 AN XY: 727246

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1112012

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:34

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:12

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1624 of the PKHD1 protein (p.Arg1624Trp). This variant is present in population databases (rs200391019, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16133180, 19914852, 26695994, 27225849; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188369). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PKHD1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Sep 08, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the PKHD1 c.4870C>T (p.Arg1624Trp) missense variant has been identified in a total of nine individuals with autosomal recessive polycystic kidney disease (ARPKD), including two siblings from a consanguineous union who presented a milder, later-onset phenotype and carried the variant in a homozygous state, six individuals who carried the variant in a compound heterozygous state and presented a range of phenotypes, and one individual with a milder, later-onset phenotype who was heterozygous for the variant (Onuchic et al. 2002; Losekoot et al. 2005; Gunay-Aygun et al. 2010). The p.Arg1624Trp variant was also identified in a heterozygous state in a total of four unaffected parents of individuals with ARPKD and was absent from 60 controls (Onuchic et al. 2002). The variant is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1624Trp variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jun 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for the c.4870C>T variant in the PKHD1 gene. This variant has been reported in the literature in several different families with autosomal recessive polycystic kidney disease (ARPKD) as both homozygous and compound heterozygous, usually associated with a late onset or milder phenotype (e.g. Onuchic et al 2002 Am J Hum Genet 70: 1305-1317; Sharp et al 2005 J Met Genet 42: 336-349; ). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.014% (40 out of 277,158 alleles). This variant is considered to be pathogenic according to the ACMG guidelines. -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_138694.3(PKHD1):c.4870C>T(R1624W) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 27225849, 16133180, 19914852 and 11898128. Classification of NM_138694.3(PKHD1):c.4870C>T(R1624W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Sep 25, 2020

Laboratory of Molecular Genetics, Children's Memorial Health Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.4870C>T (p.Arg1624Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not functional for this variant). This variant was found in 22/121594 control chromosomes at a frequency of 0.0001809, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in at least 6 ARPKD patients in heterozygous or homozygous state (Obeidova_2015, Sharp_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Pathogenic:12

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM3_strong, PP3 -

-

Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Missense variant c.4870C>T in Exon 32 of the PKHD1 gene that results in the amino acid substitution p.Arg1624Trp was identified. The observed variant has a maximum allele frequency of 0.00015/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as [Pathogenic/Likely Pathogenic/Uncertain Significance] Conflicting Interpretations [Variation ID: 188369]. The observed variation has been observed in individual(s) with autosomal recessive polycystic kidney disease (Gunay-Aygun M, et.al., 2010). For these reasons, this variant has been classified as Likely Pathogenic. -

-

Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2023

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Pathogenic for Polycystic kidney disease, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in gnomAD (PM2 downgraded to supporting); For recessive disorders, detected in trans with a pathogenic variant (PM3 upgraded to very strong; PMID: 11898128, 12506140, 12874454, 15805161, 16133180, 25701400, 26695994); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4,PM3strong,PM2,PP4 -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 28, 2025

Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino"

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.4870C>T (p.Arg1624Trp) in PKHD1 gene has been identified in a total of nine individuals with autosomal recessive polycystic kidney disease (ARPKD), including two siblings from a consanguineous union who presented a milder, later-onset phenotype and carried the variant in a homozygous state, six individuals who carried the variant in a compound heterozygous state and presented a range of phenotypes, and one individual with a milder, later-onset phenotype who was heterozygous for the variant (Gunay-Aygun et al. 2010; Losekoot et al. 2005; Onuchic et al. 2002). The p.Arg1624Trp variant was also identified in a heterozygous state in a total of four unaffected parents of individuals with ARPKD and was absent from 60 controls (Onuchic et al. 2002). The observed variant has allele frequency of 0.02% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg1624Trp in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1624 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 32949114, 34853893, 34405919, 34645488, 30586318, 31130284, 27843768, 16133180, 11898128, 25701400, 19914852, 27401137, 27894351, 27151922, 28454995, 30202406, 31844813, 32799815, 31980526, 32571524, 32574212, 32398770, 34426522, 35812281, 36177613, 37644014, 35325889, 38178268, 35715958, 37078890, 37464296, 36938085) -

Apr 17, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Arg1624Trp variant was identified in 28 of 696 proband chromosomes (frequency: 0.04) from individuals or families with ARPKD and was not identified in 200 control chromosomes from healthy individuals (Edrees 2016,Gunay-Aygun 2010, Losekoot 2005, Melchionda 2016, Obeidova 2015, Sharp 2005). The variant was also identified in dbSNP (ID: rs200391019) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, GeneDx and four clinical laboratories; as likely pathogenic by Counsyl; as uncertain significance by SIB Swiss Institute of Bioinformatics), LOVD 3.0 (3x), and in RWTH AAachen University ARPKD database (as pathogenic or probably pathogenic), databases. The variant was not identified in COGR database. The variant was identified in control databases in 40 of 277158 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 28 of 126656 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10144 chromosomes (freq: 0.0001), and South Asian in 3 of 30780 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, or Finnish populations. The p.Arg1624 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Caroli disease Pathogenic:1

May 05, 2021

Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal cyst Pathogenic:1

May 02, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant polycystic liver disease Pathogenic:1

Sep 01, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

PKHD1-related disorder Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 c.4870C>T variant is predicted to result in the amino acid substitution p.Arg1624Trp. This variant has been repeatedly reported in patients with later-onset autosomal recessive polycystic kidney disease (ARPKD), either in the homozygous state or in trans with another pathogenic PKHD1 variant (Onuchic et al. 2002. PubMed ID: 11898128; Sharp et al. 2005. PubMed ID: 15805161; Losekoot et al. 2005. PubMed ID: 16133180). This variant is reported in 0.022% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Abnormal intrahepatic bile duct morphology Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	0.052
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		4.8
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;P
Vest4		0.76
MVP		0.97
MPC		0.25
ClinPred		0.23	T
GERP RS		4.4
Varity_R		0.25
gMVP		0.59
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs200391019; hg19: chr6-51889738; COSMIC: COSV61859807;