TTYH3

Chr 7

tweety family member 3

NCBI Gene: 80727 ENSG00000136295 UniProt: Q9C0H2 OMIM: 608919

The protein functions as a calcium-activated chloride channel and volume-regulated anion channel involved in brain cell volume regulation and osmolyte transport. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and brain atrophy. This represents a rare form of early-onset epileptic encephalopathy affecting neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the tweety family of proteins. Members of this family function as chloride anion channels. The encoded protein functions as a calcium(2+)-activated large conductance chloride(-) channel. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.21

Clinical Summary— TTYH3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

91 VUS of 107 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.999

Z-score 4.68

OE 0.07 (0.03–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.81Z-score

OE missense 0.88 (0.80–0.96)

291 obs / 332.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.21)

0≤0.351.4

Missense OE?0.88 (0.80–0.96)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 2 / 29.3Missense obs/exp: 291 / 332.4Syn Z: 0.42

This gene — mechanism propensity

0.4686th %ile

GOF

0.74top 25%

LOF

0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.21

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

VUS91

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	91	0	91
Likely Benign	1	3	4
Benign	0	0	0
Total	92	3	95

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap TTYH3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →