LHFPL5

protein-coding

LHFPL tetraspan subfamily member 5, the group of LHFPL tetraspan proteins

Gene summary

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]

Previous symbols:

DFNB67

MANE transcript

NM_182548.4

Inheritance

ClinVar variants

P:24U:66B:21

Top phenotype

Deafness, autosomal recessive 67

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr6:35,797,206-35,845,397

External References & Databases

Ensembl (ENSG00000197753)

Transcript & Mutation Effects

hg38 • Region Span ~48.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012460

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The LHFPL5 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/27/2017. This association was made using case-level data only. At least 8 missense, nonsense, and frameshift variants have been reported in humans. LHFPL5 was first associated with this disease in humans as early as 2006 (Shabbir et al.). Association is seen in at least 9 probands in 6 publications (16459341, 16752389, 21816241, 19888295, 26437881, 26029705). Variants in this gene segregated with disease in 24 additional family members. This gene-disease association is supported by 2 mouse models, a fly model, expression studies and protein interaction studies. In summary, LHFPL5 is definitively associated with autosomal recessive nonsyndromic hearing loss.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012460

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012460

Submitter: G2P

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 67AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 16752389; 16459341

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LHFPL5 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 75

Autosomal recessive nonsyndromic hearing loss 67Total: 31

Inborn genetic diseasesTotal: 22

not specifiedTotal: 15

LHFPL5-related disorderTotal: 14

Hearing loss, autosomal recessiveTotal: 3

Hearing impairmentTotal: 2

DeafnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182548.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	18 clinvar		22
missense	1 clinvar	8 clinvar	60 clinvar	3 clinvar		72
nonsense	1 clinvar	3 clinvar	2 clinvar			6
start loss		1 clinvar				1
frameshift	5 clinvar	3 clinvar				8
splice donor/acceptor (+/-2bp)	2 clinvar					2
Total	9	15	66	21	0	111

Highest pathogenic variant AF is 0.000115859635

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182548.4	RefSeq	NP_872354.1	3	MANE Select
ENST00000360215.3	Ensembl	ENSP00000353346.1	3	MANE Select
ENST00000651132.1	Ensembl	ENSP00000498322.1	3	Standard
ENST00000651132.2	Ensembl	ENSP00000498322.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lhfpl5a	Danio rerio	Structure: musculoskeletal movement Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

lhfpl5a

Danio rerio

Structure: musculoskeletal movement

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ion transport

Molecular Function

protein binding

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360215
Coding exons: 3
Length: 28582
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.300	124	134	0.927	0.00000913	1430
Missense (PolyPhen)		56	64.621	0.86659		702
Synonymous	1.29	46	58.5	0.786	0.00000458	450
Loss of Function	0.724	6	8.24	0.728	4.43e-7	86

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In the inner ear, may be a component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel. Regulates transducer channel conductance and is required for fast channel adaptation (By similarity). {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 67 (DFNB67) [MIM:610265]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:16459341, ECO:0000269|PubMed:16752389, ECO:0000269|PubMed:26437881, ECO:0000269|PubMed:28281779}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.285
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.306

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium