rs727503493 — TMPRSS3 c.208delC (p.His70Thrfs*19)

TMPRSS3 c.208delC — The Frameshift That Silences the Inner Ear

Deep inside the cochlea, thousands of microscopic hair cells convert sound waves into electrical impulses. These cells depend on a molecular guardian called TMPRSS3 — a transmembrane serine protease that is indispensable for their survival from the moment hearing first activates. The c.208delC variant (rs727503493) is a one-base deletion in exon 4 of TMPRSS3 that shifts the reading frame entirely, producing a truncated, non-functional protein that terminates after only 88 amino acids instead of the full 454. When two copies of this or similarly severe mutations are inherited, cochlear hair cells degenerate before or shortly after the onset of hearing, causing permanent deafness. Carriers of a single copy face no hearing loss themselves but have a 25% risk per pregnancy if their partner also carries a pathogenic TMPRSS3 allele.

This variant was first identified as a founder mutation in the Slovenian population¹¹ identified as a founder mutation in the Slovenian population
Battelino et al. European Archives of Oto-Rhino-Laryngology, 2016 — the most common TMPRSS3 pathogenic allele in that country, found in homozygous state in 13.1% of Slovenian autosomal recessive nonsyndromic hearing loss (ARNSHL) patients tested. It has since been documented across Spanish, Greek, Dutch, Polish, Czech, and US populations. Globally, the deletion allele has a frequency of approximately 0.084% in gnomAD exomes (driven almost entirely by European carriers at 0.098%), meaning roughly 1 in 500 people of European descent carries a single copy.

The Mechanism

TMPRSS3 encodes a type II transmembrane serine protease²² type II transmembrane serine protease
A membrane-anchored enzyme with its catalytic domain on the extracellular surface; requires cleavage of its own prodomain for activation expressed in inner and outer cochlear hair cells, spiral ganglion neurons, and the stria vascularis. The c.208delC deletion removes a cytosine at codon 70 in the LDLRA (low-density lipoprotein receptor class A) domain, causing a frameshift that generates a premature stop codon after 19 altered residues: p.His70Thrfs*19. The resulting truncated protein of 88 amino acids lacks the entire serine protease catalytic domain and is presumed functionally null.

In mouse models, Tmprss3 deficiency causes hair cell degeneration beginning at postnatal day 12³³ hair cell degeneration beginning at postnatal day 12
The exact day hearing first activates in mice; degeneration starts in the high-frequency basal cochlear turn and sweeps apically within 48 hours. In humans, two null alleles cause DFNB10 — profound sensorineural hearing loss present at birth or detectable within the first year of life. When c.208delC is paired with a milder missense allele (such as p.Ala306Thr or p.Val199Met), the result is often DFNB8 — a postlingual progressive loss with childhood onset and a characteristic ski-slope audiogram pattern.

The Evidence

The severity classification of c.208delC is established across multiple independent cohort studies. Sommen et al. 2011⁴⁴ Sommen et al. 2011 formally classified this frameshift as a "severe" allele in their genotype-phenotype correlation framework: patients homozygous for two severe TMPRSS3 alleles present with prelingual profound hearing impairment (DFNB10), whereas those with one severe and one mild allele develop postlingual progressive loss (DFNB8) — typically with onset in childhood and progression at approximately 0.3–6 dB per year depending on frequency.

The Battelino cohort confirmed a uniform phenotype in Slovenian c.208delC homozygotes: all presented with profound congenital hearing loss and achieved satisfactory speech recognition after cochlear implantation. In a larger international multi-center cohort of 127 TMPRSS3 hearing loss patients⁵⁵ international multi-center cohort of 127 TMPRSS3 hearing loss patients
Colbert et al. Human Genetics 2024, cochlear implantation yielded a mean word recognition score of 76%, with age at implantation — not genotype — as the dominant predictor of outcome: each year of delay reduces speech recognition by approximately 0.3%.

In DFNB8 families carrying c.208delC compound heterozygous with a mild allele, the Dutch cohort data⁶⁶ Dutch cohort data
Sommen et al. 2011 — seven implant recipients in DFNB8 families achieved mean phoneme score of 84.1% demonstrated excellent cochlear implant outcomes with a mean phoneme score of 84.1% (SD 5.4%), substantially above control reference groups.

Looking ahead, a 2023 proof-of-concept study⁷⁷ 2023 proof-of-concept study
Mittal et al. Molecular Therapy 2023 demonstrated that a single administration of AAV-TMPRSS3 gene therapy restored auditory function in aged DFNB8 mice — the first evidence that TMPRSS3-related hearing loss may be treatable even in adulthood, opening a potential future therapeutic pathway for human carriers of severe alleles.

Practical Implications

For heterozygous carriers (one copy of c.208delC), hearing is normal — the recessive inheritance pattern means one functional TMPRSS3 allele is sufficient to maintain cochlear hair cell survival. The clinical significance of carrier status is primarily for family planning. If a carrier's reproductive partner also carries a pathogenic TMPRSS3 allele (including but not limited to c.208delC), each pregnancy carries a 25% risk of biallelic disease, a 50% chance of producing another carrier, and a 25% chance of an unaffected non-carrier child.

For individuals homozygous or compound heterozygous for two loss-of-function TMPRSS3 alleles, early audiological evaluation and prompt cochlear implantation are the standard of care. The evidence consistently shows excellent implant outcomes, and delay directly worsens speech recognition scores.

Interactions

This variant is the principal complementary allele to consider alongside rs10421919 (the TMPRSS3 near-gene tag variant in this database). An individual who tests positive for the near-gene tag and then undergoes full TMPRSS3 gene sequencing may discover c.208delC on one or both chromosomes, which directly informs severity and phenotype prediction. Compound heterozygosity for c.208delC with a milder allele such as p.Ala306Thr (rs137853000) typically produces the DFNB8 postlingual progressive phenotype rather than congenital profound deafness.

A possible digenic interaction with GJB2 (connexin 26) has been studied: initial case reports raised the possibility that single-allele TMPRSS3 + single-allele GJB2 mutations could cause hearing loss digenically, but subsequent analyses did not confirm this for the originally reported families. Current consensus favors biallelic TMPRSS3 mutations as the primary explanation in most cases, but comprehensive deafness gene panel testing — including GJB2 — is warranted when evaluating individuals with hearing loss and a single confirmed TMPRSS3 pathogenic allele.