LHFPL5

Chr 6AR

LHFPL tetraspan subfamily member 5

Also known as: DFNB67, TMHS, dJ510O8.8

NCBI Gene: 222662ENSG00000197753UniProt: Q8TAF8

This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 67MIM #610265
AR
192
ClinVar variants
31
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— LHFPL5
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 116 VUS of 192 total submissions

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.
1.43LOEUF
pLI 0.000
Z-score 0.72
OE 0.73 (0.40–1.43)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.30Z-score
OE missense 0.93 (0.80–1.08)
124 obs / 133.8 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.0.73 (0.40–1.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.80–1.08)
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.0.79
0≤1.21.6
LoF obs/exp: 6 / 8.2Missense obs/exp: 124 / 133.8Syn Z: 1.29

ClinVar Variant Classifications

192 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic13
VUS116
Likely Benign27
Benign12
Conflicting6
18
Pathogenic
13
Likely Pathogenic
116
VUS
27
Likely Benign
12
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
10
0
18
Likely Pathogenic
3
7
3
0
13
VUS
0
53
59
4
116
Likely Benign
0
1
9
17
27
Benign
0
0
12
0
12
Conflicting
—6
Total9639321192

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

View in ClinVar →

Protein Context — Lollipop Plot

LHFPL5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LHFPL5-related deafness

strong
ARLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal recessive 67

MIM #610265

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — LHFPL5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Genotype and phenotype characteristics of DFNB67 hearing loss patients with LHFPL5 variants].
Zhang J et al.·Zhonghua Yi Xue Za Zhi
2025Cohort
Expression and Clinical Significance of PIEZO2 in Gastric Cancer.
Liang T et al.·Comb Chem High Throughput Screen
2023
High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5.
Lerat J et al.·Clin Genet
2019
Novel Mutations in KCNQ4, LHFPL5 and COCH Genes in Iranian Families with Hearing Impairment.
Mehregan H et al.·Arch Iran Med
2019
Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5.
Sun L et al.·Front Med
2024
Novel missense and 3'-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment.
Liaqat K et al.·J Hum Genet
2018
Mutations in eight small DFNB genes are not a frequent cause of non-syndromic hereditary hearing loss in Czech patients.
Marková S et al.·Int J Pediatr Otorhinolaryngol
2016Cohort
Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families.
Noman M et al.·Genes (Basel)
2019
LHFPL5 mutation: A rare cause of non-syndromic autosomal recessive hearing loss.
Al-Amri AH et al.·Eur J Med Genet
2019Case report
Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.
Wang R et al.·Genet Test Mol Biomarkers
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools