TMC1

Chr 9ADAR

transmembrane channel like 1

Also known as: DFNA36, DFNB11, DFNB7

NCBI Gene: 117531 ENSG00000165091 UniProt: Q8TDI8

This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 36MIM #606705

Deafness, autosomal recessive 7MIM #600974

Active trials

Pathogenic / LP

100

ClinVar variants

Pubs (1 yr)

0.9

Missense Z

0.97

LOEUF

Clinical Summary— TMC1

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

60 Pathogenic / Likely Pathogenic· 33 VUS of 100 total submissions

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GeneReview available — TMC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.97LOEUF

pLI 0.000

Z-score 1.69

OE 0.74 (0.56–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.86Z-score

OE missense 0.88 (0.81–0.96)

350 obs / 398.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.74 (0.56–0.97)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.81–0.96)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03

0≤1.21.6

LoF obs/exp: 35 / 47.6Missense obs/exp: 350 / 398.2Syn Z: -0.26

0.7326th %ile

GOF

0.81top 10%

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

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.

Literature Evidence

GOFTwo different missense mutations, p.D572N and p.D572H, affecting the same nucleotide and codon of the TMC1 gene were earlier reported to cause autosomal dominant hearing impairment at locus DFNA36 in two North American families.PMID:19180119

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