ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.3761_3762delinsG (p.Ala1254fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138694.4(PKHD1):c.3761_3762delinsG (p.Ala1254fs)
Variation ID: 96398 Accession: VCV000096398.34
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 6p12.2 6: 52026048-52026049 (GRCh38) [ NCBI UCSC ] 6: 51890846-51890847 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 16, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.3761_3762delinsG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Ala1254fs NM_170724.3:c.3761_3762delinsG NP_733842.2:p.Ala1254fs NC_000006.12:g.52026048_52026049delinsC NC_000006.11:g.51890846_51890847delinsC NG_008753.1:g.66577_66578delinsG - Protein change
- A1254fs
- Other names
- (p.Ala1254GlyfsX49)
- p.Ala1254Glyfs*49
- Canonical SPDI
- NC_000006.12:52026047:GG:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PKHD1 | - | - |
GRCh38 GRCh37 |
4920 | 5132 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000169008.26 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2022 | RCV000790791.7 | |
PKHD1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV003407466.5 |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV002505008.2 |
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
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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. |
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Pathogenic
(Oct 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916156.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PKHD1 c.3761_3762delCCinsG (p.Ala1254GlyfsTer49) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala1254GlyfsTer49 variant has been reported … (more)
The PKHD1 c.3761_3762delCCinsG (p.Ala1254GlyfsTer49) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala1254GlyfsTer49 variant has been reported in six studies and in a total of 18 individuals with autosomal recessive polycystic kidney disease, including in three in a homozygous state, in 14 in a compound heterozygous state, and in one in a heterozygous state (Onuchic et al. 2002; Rossetti et al. 2003; Furu et al. 2003; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). The p.Ala1254GlyfsTer49 variant was absent from 510 control individuals and is not reported in the Exome Aggregation Consortium or Exome Sequencing Project or 1000 Genomes, in a region with good coverage, hence it is presumed to be rare. Based on the collective evidence, the p.Ala1254GlyfsTer49 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. (less)
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Pathogenic
(Apr 03, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000229573.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 11
Sex: mixed
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Pathogenic
(Dec 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711731.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Ala1254GlyfsX49 variant in PKHD1 has been reported in the homozygous or co mpound heterozygous state in at least 10 individuals with polycystic kidney dise … (more)
The p.Ala1254GlyfsX49 variant in PKHD1 has been reported in the homozygous or co mpound heterozygous state in at least 10 individuals with polycystic kidney dise ase and segregated with disease in 1 affected relative (Onuchic 2002, Furu 2003, Rossetti 2003, Sharp 2005, Quint 2016). It has also been identified in 0.7% (73 /10332) of Ashkenazi Jewish and 0.12% (43/35412) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 1254 and leads to a premature termination codon 49 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Loss of functi on of the PKHD1 gene is an established disease mechanism in autosomal recessive polycystic kidney disease. In summary, this variant meets criteria to be classif ied as pathogenic for autosomal recessive polycystic kidney disease. ACMG/AMP Cr iteria applied: PVS1, PM3_Very Strong; PP1. (less)
Number of individuals with the variant: 2
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Pathogenic
(May 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699862.2
First in ClinVar: Dec 26, 2017 Last updated: Nov 08, 2019 |
Comment:
Variant summary: PKHD1 c.3761_3762delinsG (p.Ala1254GlyfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PKHD1 c.3761_3762delinsG (p.Ala1254GlyfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251498 control chromosomes. c.3761_3762delinsG has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (homozygous and compound heterozygous individuals), and authors indicate the variant is a Ashkenazi Jewish founder mutation. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193890.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_138694.3(PKHD1):c.3761_3762delCCinsG(A1254Gfs*49) is classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. Sources cited for classification include the following: PMID 12846734, 12874454, … (more)
NM_138694.3(PKHD1):c.3761_3762delCCinsG(A1254Gfs*49) is classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. Sources cited for classification include the following: PMID 12846734, 12874454, 19914852, 15805161, 11898128, 15698423 and 15108277. Classification of NM_138694.3(PKHD1):c.3761_3762delCCinsG(A1254Gfs*49) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Feb 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001168568.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 2846734, 30609409, 20413436, 19914852, 11898128, 26721323, 15698423, 29327352, 30566001, 15805161, 12874454, 12846734, 15108277) (less)
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Pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004202201.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000545848.7
First in ClinVar: Aug 23, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs746972457, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This sequence change … (more)
This variant is present in population databases (rs746972457, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Ala1254Glyfs*49) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease and is commonly reported in cis with a benign variant, c.3761C>G (PMID: 11898128, 12846734, 12874454, 15805161, 26721323, 31980526). This variant is also known as c.3761_3762delinsG (p.Ala1254Glyfs*49). ClinVar contains an entry for this variant (Variation ID: 188746). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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PKHD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116008.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The PKHD1 c.3761_3762delinsG variant is predicted to result in a frameshift and premature protein termination (p.Ala1254Glyfs*49). This variant has been reported in unrelated individuals with … (more)
The PKHD1 c.3761_3762delinsG variant is predicted to result in a frameshift and premature protein termination (p.Ala1254Glyfs*49). This variant has been reported in unrelated individuals with polycystic kidney disease (Onuchic et al. 2002. PubMed ID: 11898128; Quint et al. 2015. PubMed ID: 26721323; Ceyhan-Birsoy et al. 2019. PubMed ID: 30609409). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKHD1 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: yes
Allele origin:
unknown
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001427112.2
First in ClinVar: Aug 15, 2020 Last updated: Sep 18, 2020 |
Comment:
A heterozygous frameshift deletion-insertion variant, NM_138694.3(PKHD1):c.3761_3762delinsG, has been identified in exon 32 of 37 of the PKHD1 gene. This deletion-insertion is predicted to create a … (more)
A heterozygous frameshift deletion-insertion variant, NM_138694.3(PKHD1):c.3761_3762delinsG, has been identified in exon 32 of 37 of the PKHD1 gene. This deletion-insertion is predicted to create a frameshift starting at amino acid position 1254, introducing a stop codon 49 residues downstream (NP_619639.3(PKHD1):p.(Ala1254Glyfs*49)). This variant is predicted to result in loss of protein function either through truncation (including the loss of multiple domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.04% (126/276402 heterozygotes and 0 homozygote). The variant has previously been described as pathogenic multiple times in families with polycystic kidney disease (ClinVar, Gunay-Aygun M. et al. (2010), Rosetti S. et al. (2003), Bergmann C. et al. (2005)). Furthermore, this variant has been reported as the founder mutation in the Ashkenazi population (Quint A. et al. 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Clinical Features:
Enlarged kidney (present) , Proteinuria (present) , Multiple renal cysts (present)
Secondary finding: no
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Pathogenic
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810186.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226786.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM3_very_strong, PVS1
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Polycystic kidney disease 4
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Hadassah Hebrew University Medical Center
Accession: SCV000256233.1
First in ClinVar: Aug 23, 2016 Last updated: Aug 23, 2016 |
Observation 1:
Number of individuals with the variant: 5
Clinical Features:
AR polycystic kidney disease (present)
Sex: mixed
Ethnicity/Population group: Ashkenazi jews
Geographic origin: Israel
Method: DNA sample enriched for exonic sequences, with the SureSelect Human All Exon v.2 Kit that targeted 50 Mb (Agilent Technologies, Santa Clara, California, USA). Sequencing was carried out on a HiSeq2000 (Illumina, San Diego, California, USA) and 90-bp were read paired-end. Reads alignment and variant calling were performed with DNAnexus software (Palo Alto, California, USA) using the default parameters with the human genome assembly hg19 (GRCh37) as a reference. Variants confirmed with Sanger sequencing.
Observation 2:
Number of individuals with the variant: 9
Sex: mixed
Ethnicity/Population group: Ashkenazi Jews
Geographic origin: Israel
Method: DNA sample enriched for exonic sequences, with the SureSelect Human All Exon v.2 Kit that targeted 50 Mb (Agilent Technologies, Santa Clara, California, USA). Sequencing was carried out on a HiSeq2000 (Illumina, San Diego, California, USA) and 90-bp were read paired-end. Reads alignment and variant calling were performed with DNAnexus software (Palo Alto, California, USA) using the default parameters with the human genome assembly hg19 (GRCh37) as a reference. Variants confirmed with Sanger sequencing.
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000784707.1
First in ClinVar: Jul 13, 2018 Last updated: Jul 13, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Short stature (present) , Hypermetropia (present) , Myopia (present) , Abnormality of eye movement (present) , Delusions (present) , Depressivity (present) , Increased susceptibility to … (more)
Short stature (present) , Hypermetropia (present) , Myopia (present) , Abnormality of eye movement (present) , Delusions (present) , Depressivity (present) , Increased susceptibility to fractures (present) (less)
Indication for testing: General Interest
Age: 40-49 years
Sex: female
Testing laboratory: Illumina Clinical Services Laboratory,Illumina
Date variant was reported to submitter: 2016-09-03
Testing laboratory interpretation: Pathogenic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic diagnosis and renal biopsy findings in the setting of a renal genetics clinic. | Ben Moshe Y | American journal of medical genetics. Part C, Seminars in medical genetics | 2022 | PMID: 36239278 |
Pathogenic variant-based preconception carrier screening in the Israeli Jewish population. | Davidov B | Clinical genetics | 2022 | PMID: 35315053 |
Clinical Utility of Genetic Testing in the Precision Diagnosis and Management of Pediatric Patients with Kidney and Urinary Tract Diseases. | Bekheirnia N | Kidney360 | 2020 | PMID: 35368817 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
An Ashkenazi founder mutation in the PKHD1 gene. | Quint A | European journal of medical genetics | 2016 | PMID: 26721323 |
Cost-effective PKHD1 genetic testing for autosomal recessive polycystic kidney disease. | Krall P | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 24162162 |
Correlation of kidney function, volume and imaging findings, and PKHD1 mutations in 73 patients with autosomal recessive polycystic kidney disease. | Gunay-Aygun M | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 20413436 |
Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. | Denamur E | Kidney international | 2010 | PMID: 19940839 |
PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis. | Gunay-Aygun M | Molecular genetics and metabolism | 2010 | PMID: 19914852 |
Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. | Sharp AM | Journal of medical genetics | 2005 | PMID: 15805161 |
Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). | Bergmann C | Kidney international | 2005 | PMID: 15698423 |
PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). | Bergmann C | Human mutation | 2004 | PMID: 15108277 |
Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. | Furu L | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 12874454 |
A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. | Rossetti S | Kidney international | 2003 | PMID: 12846734 |
PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. | Onuchic LF | American journal of human genetics | 2002 | PMID: 11898128 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
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Text-mined citations for rs398124484 ...
HelpRecord last updated May 19, 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.