ClinVar Genomic variation as it relates to human health
NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys)
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_001206744.2(TPO):c.2395G>A (p.Glu799Lys)
Variation ID: 4046 Accession: VCV000004046.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p25.3 2: 1503956 (GRCh38) [ NCBI UCSC ] 2: 1507728 (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 Oct 13, 2016 Oct 8, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001206744.2:c.2395G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001193673.1:p.Glu799Lys missense NM_000547.6:c.2395G>A NP_000538.3:p.Glu799Lys missense NM_001206745.2:c.2224G>A NP_001193674.1:p.Glu742Lys missense NM_175719.4:c.2224G>A NP_783650.1:p.Glu742Lys missense NM_175721.3:c.2386+7191G>A intron variant NM_175722.3:c.1876G>A NP_783653.1:p.Glu626Lys missense NC_000002.12:g.1503956G>A NC_000002.11:g.1507728G>A NG_011581.1:g.95494G>A P07202:p.Glu799Lys - Protein change
- E799K, E742K, E626K
- Other names
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- Canonical SPDI
- NC_000002.12:1503955: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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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TPO | - | - |
GRCh38 GRCh38 GRCh37 |
707 | 820 |
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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2020 | RCV000004261.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV001815161.21 |
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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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000416792.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TPO c.2395G>A (p.Glu799Lys) variant has been reported in three studies in a total of 17 individuals with congenital hypothyroidism, including 11 homozygotes from a … (more)
The TPO c.2395G>A (p.Glu799Lys) variant has been reported in three studies in a total of 17 individuals with congenital hypothyroidism, including 11 homozygotes from a large consanguineous Amish family where the variant co-segregated with disease and six unrelated compound heterozygotes (Bikker et al. 1995; Pannain et al. 1999; Avbelj et al. 2007). Control data are unavailable for the variant, which is reported at a frequency of 0.00485 in the Chinese Han in Beijing, China, population of the 1000 Genomes Project, however this is based on one allele only so the variant is presumed to be rare. In CHO-K1 cells, the p.Glu799Lys variant had similar cellular distribution and expression levels compared to wildtype but had non-detectable activity in the guaiacol assay and exhibited nonenzymatic reaction rate in iodide oxidation assay, suggesting that this variant produces inactive TPO (Bikker et al. 1997). Based on the evidence, the p.Glu799Lys variant is classified as pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Feb 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984030.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Pathogenic
(Jan 09, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004292052.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 799 of the TPO protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 799 of the TPO protein (p.Glu799Lys). This variant is present in population databases (rs121908085, gnomAD 0.0009%). This missense change has been observed in individual(s) with thyroid dyshormonogenesis (PMID: 7550241, 28444304, 34780050). 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. This variant is also known as c.2485G>A. ClinVar contains an entry for this variant (Variation ID: 4046). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063823.19
First in ClinVar: Jan 29, 2022 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Mar 01, 1999)
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no assertion criteria provided
Method: literature only
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THYROID DYSHORMONOGENESIS 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024427.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 13, 2016 |
Comment on evidence:
Pannain et al. (1999) identified a high incidence of severe hypothyroidism due to a complete iodide organification defect (TDH2A; 274500) in the youngest generation of … (more)
Pannain et al. (1999) identified a high incidence of severe hypothyroidism due to a complete iodide organification defect (TDH2A; 274500) in the youngest generation of 5 nuclear families belonging to an inbred Amish kindred. The presence of an ancestral couple 7 to 8 generations back suggested an autosomal recessive mode of inheritance. Initial studies of homozygosity by descent using 2 polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected sibs from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genomewide homozygosity screen done using DNA pools from affected and unaffected family members localized the defect close to the TPO gene. Sequencing of the TPO gene revealed 2 missense mutations, glu799 to lys (E799K) and arg648 to gln (R648Q; 606765.0009). TPO 799K was found in both alleles of the 11 affected homozygotes, and both mutations were present in each of the 3 affected compound heterozygotes, but there were no TPO mutations in 1 subject with hypothyroidism of different etiology. The authors concluded that their results demonstrated the power of the DNA pooling strategy in localizing a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population. Bikker et al. (1995) identified the E799K mutation in a Dutch family segregating total iodide organification defect. (less)
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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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Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7. | Acar S | Journal of endocrinological investigation | 2022 | PMID: 34780050 |
A frequent oligogenic involvement in congenital hypothyroidism. | de Filippis T | Human molecular genetics | 2017 | PMID: 28444304 |
High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. | Avbelj M | European journal of endocrinology | 2007 | PMID: 17468186 |
Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. | Pannain S | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10084596 |
Molecular analysis of mutated thyroid peroxidase detected in patients with total iodide organification defects. | Bikker H | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9024270 |
Identification of five novel inactivating mutations in the human thyroid peroxidase gene by denaturing gradient gel electrophoresis. | Bikker H | Human mutation | 1995 | PMID: 7550241 |
Text-mined citations for rs121908085 ...
HelpRecord last updated Oct 08, 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.