DIO1

Chr 1AD

iodothyronine deiodinase 1

Also known as: 5DI, THMA2, TXDI1

NCBI Gene: 1733 ENSG00000211452 UniProt: P49895 OMIM: 147892

The encoded protein is a selenoprotein deiodinase that catalyzes both activation and inactivation of thyroid hormones, converting thyroxine (T4) to the bioactive hormone triiodothyronine (T3) and providing most circulating T3 essential for growth, differentiation, and metabolism. Mutations cause abnormal thyroid hormone metabolism, type 2, inherited in an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.56), indicating some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the activation, as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. The activation reaction involves the conversion of the prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4), secreted by the thyroid gland, to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by 5'-deiodination. This protein provides most of the circulating T3, which is essential for growth, differentiation and basal metabolism in vertebrates. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2018]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.561 OMIM phenotype

Clinical Summary— DIO1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 23 VUS of 31 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.584

Z-score 2.56

OE 0.18 (0.07–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.48Z-score

OE missense 0.89 (0.77–1.03)

127 obs / 143.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.07–0.56)

0≤0.351.4

Missense OE?0.89 (0.77–1.03)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 2 / 11.3Missense obs/exp: 127 / 143.1Syn Z: 0.20

This gene — mechanism propensity

0.6162th %ile

GOF

0.5660th %ile

LOF

0.3549th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

31 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS23

Likely Benign3

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	0	0	0	0
VUS	0	23	0	23
Likely Benign	1	2	0	3
Benign	0	0	1	1
Total	1	27	1	29

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap DIO1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →