ClinVar Genomic variation as it relates to human health
NM_001206744.2(TPO):c.1184_1187dup (p.Ala397fs)
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.1184_1187dup (p.Ala397fs)
Variation ID: 429301 Accession: VCV000429301.39
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 2p25.3 2: 1477447-1477448 (GRCh38) [ NCBI UCSC ] 2: 1481219-1481220 (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 Apr 4, 2013 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001206744.2:c.1184_1187dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001193673.1:p.Ala397fs frameshift NM_000547.5:c.1183_1186dup NM_000547.5:c.1184_1187dupGCCG NM_000547.6:c.1184_1187dup NP_000538.3:p.Ala397fs frameshift NM_000547.6:c.1184_1187dupGCCG NM_001206745.2:c.1184_1187dup NP_001193674.1:p.Ala397fs frameshift NM_175719.4:c.1184_1187dup NP_783650.1:p.Ala397fs frameshift NM_175721.3:c.1184_1187dup NP_783652.1:p.Ala397fs frameshift NM_175722.3:c.820-7146_820-7143dup intron variant NC_000002.12:g.1477450_1477453dup NC_000002.11:g.1481222_1481225dup NG_011581.1:g.68988_68991dup - Protein change
- A397fs
- Other names
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- Canonical SPDI
- NC_000002.12:1477447:CGGCCG:CGGCCGGCCG
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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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- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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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TPO | - | - |
GRCh38 GRCh38 GRCh37 |
702 | 815 |
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
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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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000494448.25 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000779280.15 | |
TPO-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 28, 2023 | RCV003932797.1 |
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
(May 30, 2017)
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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: SCV000708760.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 31, 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: SCV000915859.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The TPO c.1184_1187dupGCCG (p.Ala397ProfsTer76) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala397ProfsTer76 variant has been reported … (more)
The TPO c.1184_1187dupGCCG (p.Ala397ProfsTer76) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala397ProfsTer76 variant has been reported in at least five studies of individuals with congenital hypothyroidism and goiter, and is found in a total of 24 affected individuals from 17 families, including in a homozygous state in 13 individuals, in a compound heterozygous state in four individuals, and in a heterozygous state in seven individuals in whom a second variant was not identified (Abramowicz et al. 1992; Avbelj et al. 2007; Altmann et al. 2013; Cangul et al. 2015; Lof et al. 2016). The variant is also found in a heterozygous state in two unaffected individuals (Avbelj et al. 2007). Three families showed segregation of the variant with the disorder in a manner consistent with autosomal recessive inheritance (Avbelj et al. 2007; Cangul et al. 2015). The p.Ala397ProfsTer76 variant was absent from 50 controls but is reported at a frequency of 0.001576 in the European (Finnish) population of the Genome Aggregation Database. Based on the evidence and potential impact of frameshift variants, the p.Ala397ProfsTer76 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
(Apr 23, 2019)
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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: SCV001362032.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TPO c.1184_1187dupGCCG (p.Ala397ProfsX76) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TPO c.1184_1187dupGCCG (p.Ala397ProfsX76) 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. The variant allele was found at a frequency of 0.0005268 in 151866 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TPO causing Deficiency of iodide peroxidase (0.0005268 vs 0.0071). c.1184_1187dupGCCG has been reported in the literature in multiple individuals affected with congenital hypothyroidism and iodide organification defect (Makretskaya_2018, Cangul_2015, Rodrigues_2005, Abramowicz_1992). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in very low residual TPO activity (5% of a normal control) (Abramowicz_1992). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369563.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP4.
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Pathogenic
(Feb 01, 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:
maternal
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515282.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
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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: SCV002568217.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PVS1 PM3_Strong PS3_Supportive
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Pathogenic
(Mar 29, 2022)
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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: SCV000581832.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
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: 17468186, 27617131, 27373559, 30240412, 29546359, 23512414, 15745925, 1401057, 11061528, 31430255, 31980526, 31589614, 32765423, 33726816) (less)
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of iodide peroxidase
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841596.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000429301 / PMID: 1401057). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Tremor (present) , Dystonic disorder (present) , Anxiety (present) , Depression (present) , Congenital hypothyroidism (present)
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Pathogenic
(Nov 11, 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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Revvity Omics, Revvity
Accession: SCV002022399.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 28, 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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Invitae
Accession: SCV003292692.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala397Profs*76) in the TPO gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ala397Profs*76) in the TPO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPO are known to be pathogenic (PMID: 11061528, 23236987, 25564141). This variant is present in population databases (rs763941231, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of thyroid dyshormonogenesis (PMID: 15745925, 27373559, 27617131, 29546359, 32765423). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1182_1183insCGGC, 1183_1186dupGGCC. ClinVar contains an entry for this variant (Variation ID: 429301). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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TPO-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004758790.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TPO c.1184_1187dupGCCG variant is predicted to result in a frameshift and premature protein termination (p.Ala397Profs*76). This variant (also known as 1273_1276dupGGCC) has been reported … (more)
The TPO c.1184_1187dupGCCG variant is predicted to result in a frameshift and premature protein termination (p.Ala397Profs*76). This variant (also known as 1273_1276dupGGCC) has been reported in multiple individuals with autosomal recessive congenital hypothyroidism (see for example, Abramowicz et al. 1992. PubMed ID: 1401057; Cangul et al. 2015. PubMed ID: 27617131; Table 1, Zou et al. 2018. PubMed ID: 29546359). This variant is reported in 0.16% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in TPO are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 31, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090916.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Likely pathogenic
(May 01, 2022)
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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: SCV004138470.8
First in ClinVar: Nov 20, 2023 Last updated: Aug 04, 2024 |
Comment:
TPO: PVS1
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2000)
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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: SCV000024421.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Abramowicz et al. (1992) demonstrated homozygosity for a 4-bp, frameshift-causing mutation in exon 8 of the TPO gene in an adopted boy with a partial … (more)
Abramowicz et al. (1992) demonstrated homozygosity for a 4-bp, frameshift-causing mutation in exon 8 of the TPO gene in an adopted boy with a partial iodide organification defect (TDH2A; 274500). The child presented with florid hypothyroidism at the age of 4 months; because of poor compliance with thyroxine treatment, he developed a large goiter with compressive symptoms requiring partial resection at the age of 12 years. The 4-bp insertion at position 1227 was due to duplication of a GGCC tetranucleotide. Bakker et al. (2000) found that a GGCC insertion in exon 8 at nucleotide 1277, leading to an early termination signal in exon 9, was the most frequently occurring mutation in 45 patients (35 families) with congenital hypothyroidism due to a total iodide organification defect (see 274500). (less)
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Pathogenic
(-)
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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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920535.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001962830.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia. | Zdraveska N | Frontiers in endocrinology | 2020 | PMID: 32765423 |
High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism. | Makretskaya N | PloS one | 2018 | PMID: 30240412 |
Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis. | Zou M | The Journal of clinical endocrinology and metabolism | 2018 | PMID: 29546359 |
Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort. | Löf C | Thyroid : official journal of the American Thyroid Association | 2016 | PMID: 27373559 |
A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family. | Cangul H | Journal of pediatric genetics | 2015 | PMID: 27617131 |
Prevalence of c.2268dup and detection of two novel alterations, c.670_672del and c.1186C>T, in the TPO gene in a cohort of Malaysian-Chinese with thyroid dyshormonogenesis. | Lee CC | BMJ open | 2015 | PMID: 25564141 |
Congenital goitrous primary hypothyroidism in two German families caused by novel thyroid peroxidase (TPO) gene mutations. | Altmann K | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2013 | PMID: 23512414 |
Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. | Cangul H | Clinical endocrinology | 2013 | PMID: 23236987 |
High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. | Avbelj M | European journal of endocrinology | 2007 | PMID: 17468186 |
Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism. | Rodrigues C | European journal of endocrinology | 2005 | PMID: 15745925 |
Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). | Bakker B | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 11061528 |
Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. | Abramowicz MJ | The Journal of clinical investigation | 1992 | PMID: 1401057 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TPO | - | - | - | - |
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Text-mined citations for rs763941231 ...
HelpRecord last updated Aug 04, 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.
NCBI staff provided an HGVS expession for allelic variant 606765.0001 based from the sequence reported in Figure 2 of the paper by Abramowicz et al., 1992 (PubMed 1401057).