This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)
Variation ID: 188896 Accession: VCV000188896.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p12.3 6: 51659682 (GRCh38) [ NCBI UCSC ] 6: 51524480 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Oct 8, 2024 Aug 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_138694.4:c.10444C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Arg3482Cys missense NC_000006.12:g.51659682G>A NC_000006.11:g.51524480G>A NG_008753.1:g.432944C>T P08F94:p.Arg3482Cys - Protein change
- R3482C
- Other names
- -
- Canonical SPDI
- NC_000006.12:51659681:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PKHD1 | - | - |
GRCh38 GRCh37 |
5041 | 5256 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2024 | RCV000169255.14 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 9, 2024 | RCV001331692.5 | |
|
PKHD1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 17, 2023 | RCV003937523.2 |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2024 | RCV000726420.10 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163015.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
|
Likely pathogenic
(Jul 23, 2014)
|
criteria provided, single submitter
Method: literature only
|
Polycystic kidney disease, infantile type
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220543.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754646.6
First in ClinVar: May 03, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001523788.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000344513.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely pathogenic
(Jan 01, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: no
Allele origin:
germline
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965800.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
|
|
|
Pathogenic
(Jul 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807434.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting
Number of individuals with the variant: 1
Clinical Features:
Gastric varix (present) , Decreased body weight (present) , Congenital hepatic fibrosis (present) , Autosomal dominant polycystic liver disease (present) , Hypertensive disorder (present) , … (more)
Gastric varix (present) , Decreased body weight (present) , Congenital hepatic fibrosis (present) , Autosomal dominant polycystic liver disease (present) , Hypertensive disorder (present) , Polycystic kidney disease (present) , Renal cyst (present) , Esophageal varix (present) , Short stature (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042824.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney … (more)
The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Advanced 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 expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the kidney (present)
|
|
|
Pathogenic
(Aug 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001805444.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024 |
Comment:
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: 26721323, … (more)
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: 26721323, 12506140, 15108277, 15698423, 19914852, 26385851, 25114813, 15805161, 19940839, 34426522, 33940108, 15108281, 30275481, 37013475, 35812281, Corradi2022[abstract], 36964991) (less)
|
|
|
Pathogenic
(Nov 17, 2023)
|
no assertion criteria provided
Method: clinical testing
|
PKHD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004747648.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal … (more)
The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2003. PubMed ID: 12506140; Thakur et al. 2014. PubMed ID: 25114813; Quint et al. 2015. PubMed ID: 26721323). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524480-G-A). This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting
Comment:
The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Advanced 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 expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 26721323, 12506140, 15108277, 15698423, 19914852, 26385851, 25114813, 15805161, 19940839, 34426522, 33940108, 15108281, 30275481, 37013475, 35812281, Corradi2022[abstract], 36964991)
Comment:
The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2003. PubMed ID: 12506140; Thakur et al. 2014. PubMed ID: 25114813; Quint et al. 2015. PubMed ID: 26721323). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524480-G-A). This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting
Comment:
The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Advanced 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 expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 26721323, 12506140, 15108277, 15698423, 19914852, 26385851, 25114813, 15805161, 19940839, 34426522, 33940108, 15108281, 30275481, 37013475, 35812281, Corradi2022[abstract], 36964991)
Comment:
The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2003. PubMed ID: 12506140; Thakur et al. 2014. PubMed ID: 25114813; Quint et al. 2015. PubMed ID: 26721323). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524480-G-A). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| An Ashkenazi founder mutation in the PKHD1 gene. | Quint A | European journal of medical genetics | 2016 | PMID: 26721323 |
| Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations. | Courcet JB | American journal of medical genetics. Part A | 2015 | PMID: 26385851 |
| Novel Mutation in the PKHD1 Gene Diagnosed Prenatally in a Fetus with Autosomal Recessive Polycystic Kidney Disease. | Thakur P | Case reports in genetics | 2014 | PMID: 25114813 |
| Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. | Denamur E | Kidney international | 2010 | PMID: 19940839 |
| Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. | Sharp AM | Journal of medical genetics | 2005 | PMID: 15805161 |
| PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD). | Bergmann C | Human mutation | 2004 | PMID: 15108281 |
| Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). | Bergmann C | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 12506140 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
Text-mined citations for rs148617572 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.