ClinVar Genomic variation as it relates to human health
NM_001206744.2(TPO):c.2578G>A (p.Gly860Arg)
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.2578G>A (p.Gly860Arg)
Variation ID: 1254323 Accession: VCV001254323.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p25.3 2: 1516942 (GRCh38) [ NCBI UCSC ] 2: 1520714 (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 Sep 19, 2021 Feb 4, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001206744.2:c.2578G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001193673.1:p.Gly860Arg missense NM_000547.6:c.2578G>A NP_000538.3:p.Gly860Arg missense NM_001206745.2:c.2407G>A NP_001193674.1:p.Gly803Arg missense NM_175719.4:c.2407G>A NP_783650.1:p.Gly803Arg missense NM_175721.3:c.2446G>A NP_783652.1:p.Gly816Arg missense NM_175722.3:c.2059G>A NP_783653.1:p.Gly687Arg missense NC_000002.12:g.1516942G>A NC_000002.11:g.1520714G>A NG_011581.1:g.108480G>A - Protein change
- G687R, G803R, G816R, G860R
- Other names
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- Canonical SPDI
- NC_000002.12:1516941: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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 | ||
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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 |
683 | 792 |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV001653105.7 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV002280187.8 |
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
(Jun 15, 2022)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002568221.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PS3 PM3_Strong PM1
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Likely pathogenic
(Oct 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811561.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 06, 2023)
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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: SCV001871281.2
First in ClinVar: Sep 19, 2021 Last updated: Sep 22, 2023 |
Comment:
Published functional studies demonstrate a damaging effect resulting in a nonfunctional protein and markedly reduced H202-producing activity (Narumi et al., 2011); In silico analysis supports … (more)
Published functional studies demonstrate a damaging effect resulting in a nonfunctional protein and markedly reduced H202-producing activity (Narumi et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also described as c.2669 G>A; This variant is associated with the following publications: (PMID: 34200080, 29650690, 32088313, 22919382, 21900383, 28867693, 28176629, 29790453, 32425884, 31867598, 17468186, 27535533) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100584.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Oct 03, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122330.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: TPO c.2578G>A (p.Gly860Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: TPO c.2578G>A (p.Gly860Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 359470 control chromosomes (gnomAD, jMorp databases (Tadaka_2021)). This frequency is not significantly higher than estimated for a pathogenic variant in TPO causing Deficiency Of Iodide Peroxidase (5.6e-05 vs 0.0071), allowing no conclusion about variant significance. c.2578G>A has been reported in the literature in both compound heterozygous and homozygous individuals affected with Deficiency Of Iodide Peroxidase (e.g., Avbelj_2007, Narumi_2011, Zhang_2020, Hashemipour_2012). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g., Narumi_2011, Zhang_2020). The most pronounced variant effect results in <10% of normal enzymatic activity. The following publications have been ascertained in the context of this evaluation (PMID: 17468186, 22919382, 21900383, 32088313, 33179747). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 16, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002020270.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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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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jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. | Tadaka S | Nucleic acids research | 2021 | PMID: 33179747 |
The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism. | Zhang RJ | Molecular and cellular endocrinology | 2020 | PMID: 32088313 |
Thyroid peroxidase gene mutation in patients with congenital hypothyroidism in isfahan, iran. | Hashemipour M | International journal of endocrinology | 2012 | PMID: 22919382 |
Molecular basis of thyroid dyshormonogenesis: genetic screening in population-based Japanese patients. | Narumi S | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21900383 |
High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. | Avbelj M | European journal of endocrinology | 2007 | PMID: 17468186 |
Text-mined citations for rs556552435 ...
HelpRecord last updated Apr 06, 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.