ClinVar Genomic variation as it relates to human health
NM_001009944.3(PKD1):c.6749C>T (p.Thr2250Met)
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.
Uncertain significance(1); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001009944.3(PKD1):c.6749C>T (p.Thr2250Met)
Variation ID: 447996 Accession: VCV000447996.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2108418 (GRCh38) [ NCBI UCSC ] 16: 2158419 (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 Dec 19, 2017 Apr 15, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001009944.3:c.6749C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001009944.3:p.Thr2250Met missense NM_000296.4:c.6749C>T NP_000287.4:p.Thr2250Met missense NC_000016.10:g.2108418G>A NC_000016.9:g.2158419G>A NG_008617.1:g.32481C>T - Protein change
- T2250M
- Other names
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- Canonical SPDI
- NC_000016.10:2108417:G:A
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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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0.00140 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00125
1000 Genomes Project 0.00140
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208
Exome Aggregation Consortium (ExAC) 0.00220
The Genome Aggregation Database (gnomAD) 0.00222
The Genome Aggregation Database (gnomAD), exomes 0.00232
Trans-Omics for Precision Medicine (TOPMed) 0.00274
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
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. |
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PKD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3118 | 3617 |
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. |
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Benign (1) |
criteria provided, single submitter
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Mar 24, 2017 | RCV000517469.3 | |
Benign (4) |
criteria provided, single submitter
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Jan 1, 2024 | RCV000658732.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000989454.13 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001292268.3 |
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. |
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Benign
(Mar 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000614521.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease, adult type
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139784.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Feb 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease, adult type
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885918.2
First in ClinVar: Feb 17, 2019 Last updated: Feb 09, 2020 |
Comment:
The PKD1 c.6749C>T, p.Thr2250Met variant (rs139971481) has been reported in individuals diagnosed with ADPKD (Irazabal 2011, Perrichot 2000, Reiterova 2013, Rossetti 2012) but has also … (more)
The PKD1 c.6749C>T, p.Thr2250Met variant (rs139971481) has been reported in individuals diagnosed with ADPKD (Irazabal 2011, Perrichot 2000, Reiterova 2013, Rossetti 2012) but has also been found to co-occur with truncating PKD1 variants (Mayo ADPKD database). In one individual, the p.Thr2250Met variant was found in-trans with a truncating PKD1 variant and correlated with a more severe polycystic disorder, suggesting a possible modifier effect (Reiterova 2013). Individuals heterozygous for this variant exhibit either a mild cystic disease or no clinical phenotypes (Kleffman 2012, Reiterova 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.35% (444/127104 alleles, including three homozygotes) in the Genome Aggregation Database. The threonine at codon 2250 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the population frequency and clinical phenotypes suggest that the p.Thr2250Met may not be a causative variant on its own, its potential effect as a disease modifier cannot be excluded. Thus, the clinical significance of p.Thr2250Met cannot be determined with certainty. References: Mayo ADPKD database: http://pkdb.mayo.edu/ Irazabal M et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011 Jun;6(6):1274-85. Kleffman J et al. Dosage-sensitive network in polycystic kidney and liver disease: multiple mutations cause severe hepatic and neurological complications. J Hepatol. 2012 Aug;57(2):476-7. Perrichot R et al. Novel mutations in the duplicated region of PKD1 gene. Eur J Hum Genet. 2000 May;8(5):353-9. Reiterova J et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013 Mar 15;14:59. (less)
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Benign
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780519.10
First in ClinVar: Jul 09, 2018 Last updated: Apr 15, 2024 |
Comment:
PKD1: BS1, BS2
Number of individuals with the variant: 4
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Polycystic Kidney disease
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001480927.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKD1 p.Thr2250Met variant was identified in 9 of 932 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Irazabal 2011, Paul 2014, Perrichot … (more)
The PKD1 p.Thr2250Met variant was identified in 9 of 932 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Irazabal 2011, Paul 2014, Perrichot 2000, Rossetti 2012). The variant was also identified in dbSNP (ID: rs139971481) as “N/A”, the ADPKD Mutation Database (classified as likely neutral) and PKD1-LOVD 3.0 (classified as unknown effect). This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 24 of 8584 European American and in 3 of 4388 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) in 262 (4 homozygous) of 119152 chromosomes (freq. 0.002) in the following populations: European in 204 of 64980 chromosomes (freq. 0.003), Latino in 26 of 11528 chromosomes (freq. 0.002), Asian in 26 of 16500 chromosomes (freq. 0.002), African in 3 of 10108 chromosomes (freq. 0.0003), Finnish in 2 of 6588 chromosomes (freq. 0.0003) and Other in 1 of 880 chromosomes (freq. 0.001), increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Thr2250 residue is 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In two different case studies suggest the variant has a dosage effect and is most likely an incompletely penetrant allele (Kleffmann 2012, Reiterova 2013). However in the Kleffman study they report a 39 year old female homozygous for the p.The2250Met variant who does not have kidney cysts, suggesting that this variant may not cause typical polycystic kidney disease. This variant located in the REJ domain of PC-1 and cleavage of PC-1 at the GPS site can be affected by variants in this domain, however, analysis by Paul (2014) did not show that p.Thr2250Met variant influences this cleavage. 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 benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 5
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926690.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968017.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036168.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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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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Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. | Paul BM | Kidney international | 2014 | PMID: 23760289 |
Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. | Reiterová J | BMC nephrology | 2013 | PMID: 23496908 |
Dosage-sensitive network in polycystic kidney and liver disease: multiple mutations cause severe hepatic and neurological complications. | Kleffmann J | Journal of hepatology | 2012 | PMID: 22406737 |
Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. | Rossetti S | Journal of the American Society of Nephrology : JASN | 2012 | PMID: 22383692 |
Cystogenic potential of CD133+ progenitor cells of human polycystic kidneys. | Carvalhosa R | The Journal of pathology | 2011 | PMID: 21706482 |
Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. | Irazabal MV | Clinical journal of the American Society of Nephrology : CJASN | 2011 | PMID: 21551026 |
Novel mutations in the duplicated region of PKD1 gene. | Perrichot R | European journal of human genetics : EJHG | 2000 | PMID: 10854095 |
Text-mined citations for rs139971481 ...
HelpRecord last updated Apr 15, 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.