NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys) AND Deficiency of iodide peroxidase

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 20, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004261.11

Allele description [Variation Report for NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys)]

NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys)

Gene:

TPO:thyroid peroxidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p25.3

Genomic location:

Preferred name:

NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys)

HGVS:

NC_000002.12:g.1503956G>A
NG_011581.1:g.95494G>A
NM_000547.6:c.2395G>A
NM_001206744.2:c.2395G>AMANE SELECT
NM_001206745.2:c.2224G>A
NM_175719.4:c.2224G>A
NM_175721.3:c.2386+7191G>A
NM_175722.3:c.1876G>A
NP_000538.3:p.Glu799Lys
NP_000538.3:p.Glu799Lys
NP_001193673.1:p.Glu799Lys
NP_001193674.1:p.Glu742Lys
NP_783650.1:p.Glu742Lys
NP_783653.1:p.Glu626Lys
NC_000002.11:g.1507728G>A
NM_000547.5:c.2395G>A
P07202:p.Glu799Lys

Protein change:

E626K; GLU799LYS

Links:

UniProtKB: P07202#VAR_006062; OMIM: 606765.0007; dbSNP: rs121908085

NCBI 1000 Genomes Browser:

rs121908085

Molecular consequence:

NM_175721.3:c.2386+7191G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000547.6:c.2395G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001206744.2:c.2395G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001206745.2:c.2224G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175719.4:c.2224G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175722.3:c.1876G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of iodide peroxidase (TDH2A)
Synonyms:: HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 2A; IODIDE PEROXIDASE DEFICIENCY; THYROID HORMONOGENESIS, GENETIC DEFECT IN, 2A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010133; MedGen: C1291299; Orphanet: 95716; OMIM: 274500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024427	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1999)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10084596, 7550241
SCV000416792	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7550241, 17468186, 9024270, 10084596 Citation Link,
SCV001984030	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024427

OMIM

no assertion criteria provided

Pathogenic
(Mar 1, 1999)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000416792

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Apr 28, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001984030

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 20, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of five novel inactivating mutations in the human thyroid peroxidase gene by denaturing gradient gel electrophoresis.

Bikker H, Vulsma T, Baas F, de Vijlder JJ.

Hum Mutat. 1995;6(1):9-16.

PubMed [citation]

PMID:: 7550241

High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis.

Avbelj M, Tahirovic H, Debeljak M, Kusekova M, Toromanovic A, Krzisnik C, Battelino T.

Eur J Endocrinol. 2007 May;156(5):511-9.

PubMed [citation]

PMID:: 17468186

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000024427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000416792.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV001984030.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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