Thyroid dyshormonogenesis 3

Summary

Thyroid dyshormonogenesis 3 (MONDO:0010135) is a disease caused by TG (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: TG (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 380
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 3
Mondo ID	MONDO:0010135
MeSH	C562769
OMIM	274700
DOID	DOID:0112187
SNOMED CT	23536000
UMLS	C0342194
MedGen	90976
GARD	0018190
Is cancer (heuristic)	no

Also known as: familial thyroid dyshormonogenesis caused by mutation in TG · hypothyroidism, congenital, due to dyshormonogenesis, 3 · TDH3 · TG familial thyroid dyshormonogenesis · thyroid dyshormonogenesis 3 · thyroid dyshormonogenesis type 3 · thyroid hormonogenesis, genetic defect in, 3

Data availability: 380 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › hypothyroidism › congenital hypothyroidism › familial thyroid dyshormonogenesis › thyroid dyshormonogenesis 3

Related subtypes (5): thyroid dyshormonogenesis 2A, thyroid dyshormonogenesis 4, thyroid dyshormonogenesis 5, thyroid dyshormonogenesis 6, thyroid dyshormonogenesis 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

380 retrieved; paginated sample, class counts are floors:

128 uncertain significance, 116 conflicting classifications of pathogenicity, 44 likely pathogenic, 29 pathogenic, 29 benign, 23 benign/likely benign, 10 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028100	NM_003235.5(TG):c.475C>T (p.Arg159Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028102	NM_003235.5(TG):c.8055G>A (p.Trp2685Ter)	TG	Pathogenic	criteria provided, single submitter
12689	NM_003235.5(TG):c.275-3C>G	TG	Pathogenic	no assertion criteria provided
12691	NM_003235.5(TG):c.4588C>T (p.Arg1530Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12693	NM_003235.5(TG):c.3733T>C (p.Cys1245Arg)	TG	Pathogenic	no assertion criteria provided
12694	NM_003235.5(TG):c.5986T>A (p.Cys1996Ser)	TG	Pathogenic	no assertion criteria provided
12695	NM_003235.5(TG):c.886C>T (p.Arg296Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12699	NM_003235.5(TG):c.1143del (p.Tyr382fs)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12700	NM_003235.5(TG):c.6725G>A (p.Arg2242His)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12701	NM_003235.5(TG):c.6200-1G>C	TG	Pathogenic	no assertion criteria provided
12702	NM_003235.5(TG):c.3229T>C (p.Cys1077Arg)	TG	Pathogenic	no assertion criteria provided
12703	NM_003235.5(TG):c.7123G>A (p.Gly2375Arg)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12706	NM_003235.5(TG):c.638+1G>A	TG	Pathogenic	no assertion criteria provided
1323687	NM_003235.5(TG):c.6397+2T>A	TG	Pathogenic	criteria provided, single submitter
1802151	NM_003235.5(TG):c.6610del (p.Ser2204fs)	TG	Pathogenic	criteria provided, single submitter
1803164	NM_003235.5(TG):c.6185G>A (p.Trp2062Ter)	TG	Pathogenic	criteria provided, single submitter
208619	NM_003235.5(TG):c.5184C>A (p.Cys1728Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218239	NM_003235.5(TG):c.638+5G>A	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434134	NM_003235.5(TG):c.2311C>T (p.Gln771Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2713686	NM_003235.5(TG):c.416G>A (p.Trp139Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735213	NM_003235.5(TG):c.274+2T>G	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735215	NM_003235.5(TG):c.1348del (p.Ser450fs)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2735216	NM_003235.5(TG):c.1351C>T (p.Arg451Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2834805	NM_003235.5(TG):c.3231C>A (p.Cys1077Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286402	NM_003235.5(TG):c.6379C>T (p.Arg2127Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
2910224	NM_003235.5(TG):c.961C>T (p.Arg321Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
3595243	NM_003235.5(TG):c.115G>T (p.Glu39Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595254	NM_003235.5(TG):c.1911G>A (p.Trp637Ter)	TG	Pathogenic	criteria provided, single submitter
3595263	NM_003235.5(TG):c.3871C>T (p.Gln1291Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595271	NM_003235.5(TG):c.6391_6394del (p.Leu2131fs)	TG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TG	Strong	Autosomal recessive	thyroid dyshormonogenesis 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	gencc,clinvar
SLA	HGNC:10902	ENSG00000155926	Q13239	Src-like-adapter	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
SLA	Src-like-adapter	Adapter protein, which negatively regulates T-cell receptor (TCR) signaling.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
SLA	Scaffold/PPI	no		SH2, SH3_domain, SLAP_SH2
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
blood	1
cortical plate	1
ganglionic eminence	1
ileal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SLA	253	broad	marker	cortical plate, blood, ganglionic eminence
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLA	2,039
SEPSECS	1,756
TG	1,493

Intra-cohort edges

A	B	Sources
SLA	TG	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SEPSECS	Q9HD40	7
TG	P01266	3
SLA	Q13239	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of FLT3	1	356.9×	0.022	SLA
FLT3 Signaling	1	173.0×	0.023	SLA
Selenoamino acid metabolism	1	98.5×	0.027	SEPSECS
Selenocysteine synthesis	1	60.1×	0.033	SEPSECS
Metabolism of amino acids and derivatives	1	33.8×	0.047	SEPSECS
Cytokine Signaling in Immune system	1	20.4×	0.065	SLA
Immune System	1	6.5×	0.165	SLA
Metabolism	1	5.8×	0.165	SEPSECS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	2808.7×	0.003	SEPSECS
iodide transport	1	802.5×	0.005	TG
selenocysteine incorporation	1	624.1×	0.005	SEPSECS
hormone biosynthetic process	1	468.1×	0.005	TG
thyroid hormone generation	1	330.4×	0.005	TG
regulation of myelination	1	295.6×	0.005	TG
thyroid gland development	1	181.2×	0.007	TG
regulation of MAPK cascade	1	151.8×	0.007	SLA
signal transduction	2	10.7×	0.011	TG, SLA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TG	0	0
SLA	0	0
SEPSECS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SEPSECS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TG, SLA

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TG	0	—
SLA	0	—
SEPSECS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns