TTC34

Chr 1

tetratricopeptide repeat domain 34

NCBI Gene: 100287898 ENSG00000215912 UniProt: A8MYJ7

TTC34 encodes a protein containing tetratricopeptide repeat domains that functions in protein-protein interactions and cellular processes. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and developmental regression. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

Research

ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.65

Clinical Summary— TTC34

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

128 VUS of 146 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.65LOEUF

pLI 0.000

Z-score -0.29

OE 1.08 (0.72–1.65)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.27Z-score

OE missense 0.96 (0.87–1.05)

295 obs / 308.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.08 (0.72–1.65)

0≤0.351.4

Missense OE?0.96 (0.87–1.05)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 15 / 13.9Missense obs/exp: 295 / 308.3Syn Z: 1.29

This gene — mechanism propensity

0.6064th %ile

GOF

0.74top 25%

LOF

0.3260th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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.

ClinVar Variant Classifications

146 submitted variants in ClinVar

ClinVar

Classification Summary

VUS128

Likely Benign13

128

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	128	0	128
Likely Benign	10	3	13
Benign	0	0	0
Total	138	3	141

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 154) ClinVar copy-number / structural variants overlap TTC34 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →