NM_203395.3(IYD):c.347T>C (p.Ile116Thr) AND Iodotyrosine deiodination defect

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 5, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000000775.3

Allele description [Variation Report for NM_203395.3(IYD):c.347T>C (p.Ile116Thr)]

NM_203395.3(IYD):c.347T>C (p.Ile116Thr)

Gene:

IYD:iodotyrosine deiodinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q25.1

Genomic location:

Preferred name:

NM_203395.3(IYD):c.347T>C (p.Ile116Thr)

HGVS:

NC_000006.12:g.150389520T>C
NG_016007.2:g.25629T>C
NM_001164694.2:c.347T>C
NM_001164695.2:c.347T>C
NM_001318495.2:c.124+45T>C
NM_203395.3:c.347T>CMANE SELECT
NP_001158166.1:p.Ile116Thr
NP_001158167.1:p.Ile116Thr
NP_981932.1:p.Ile116Thr
NC_000006.11:g.150710656T>C
NG_016007.1:g.25629T>C
NR_134655.2:n.367T>C
Q6PHW0:p.Ile116Thr

Protein change:

I116T; ILE116THR

Links:

UniProtKB: Q6PHW0#VAR_045965; OMIM: 612025.0003; dbSNP: rs121918139

NCBI 1000 Genomes Browser:

rs121918139

Molecular consequence:

NM_001318495.2:c.124+45T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001164694.2:c.347T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001164695.2:c.347T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_203395.3:c.347T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_134655.2:n.367T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Iodotyrosine deiodination defect (TDH4)
Synonyms:: DEIODINASE DEFICIENCY; HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 4; IODOTYROSINE DEHALOGENASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010136; MedGen: C0342195; Orphanet: 95716; OMIM: 274800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020925	OMIM	no assertion criteria provided	Pathogenic (Apr 24, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV005077340	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020925

OMIM

no assertion criteria provided

Pathogenic
(Apr 24, 2008)

germline

literature only

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

SCV005077340

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 5, 2024)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Mutations in the iodotyrosine deiodinase gene and hypothyroidism.

Moreno JC, Klootwijk W, van Toor H, Pinto G, D'Alessandro M, Lèger A, Goudie D, Polak M, Grüters A, Visser TJ.

N Engl J Med. 2008 Apr 24;358(17):1811-8. doi: 10.1056/NEJMoa0706819.

PubMed [citation]

PMID:: 18434651

Details of each submission

From OMIM, SCV000020925.1

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

Description

In a 9-year-old boy born in France to first-cousin parents of Moroccan descent, who was diagnosed with nonautoimmune hypothyroidism and goiter at age 8 years and had an elevated serum diiodotyrosine level (TDH4; 274800), Moreno et al. (2008) identified homozygosity for a 347T-C transition in exon 2 of the IYD gene, resulting in an ile116-to-thr (I116T) substitution in the nitroreductase domain of DEHAL1 but outside the flavin mononucleotide-binding pocket. The parents were euthyroid and had no goiter. The mutation was not found in 118 control chromosomes. Functional studies in mammalian cells revealed that the mutation markedly reduced the capacity of DEHAL1 to deiodinate mono- and diiodotyrosine, although there was some residual activity (4% and 2.5%, respectively).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005077340.1

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

Description

Variant summary: IYD c.347T>C (p.Ile116Thr) results in a non-conservative amino acid change located in the Nitroreductase domain (IPR029479) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251418 control chromosomes. c.347T>C has been reported in the literature in at least one homozygous individual with clinical features consistent with Iodotyrosine deiodination defect (ie.g. Moreno_2008). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing severely reduced deiodination ability in an in vitro iodotyrosine deiodination assay (e.g. Moreno_2008). The following publication has been ascertained in the context of this evaluation (PMID: 18434651). ClinVar contains an entry for this variant (Variation ID: 739). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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

Last Updated: Jul 23, 2024

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