LOXHD1

protein-coding

lipoxygenase homology PLAT domains 1

Gene summary

This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

Previous symbols:

DFNB77

MANE transcript

NM_001384474.1

Inheritance

AR, AD

ClinVar variants

P:506U:881B:1055

Top phenotype

Deafness, autosomal recessive 77

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr18:46,476,972-46,657,220

External References & Databases

Ensembl (ENSG00000167210)

Transcript & Mutation Effects

hg38 • Region Span ~180.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 77STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013119

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 77DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013119

Submitter: Natera

autosomal recessive nonsyndromic hearing loss 77STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013119

Submitter: PanelApp Australia

Fuchs' endothelial dystrophyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005321

Submitter: Illumina

autosomal recessive nonsyndromic hearing loss 77DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013119

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 77DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013119

Submitter: G2P

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between LOXHD1 and autosomal recessive nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/15/2017. Variants in LOXHD1 were first reported in humans with this disease as early as 2009 (Grillet et al., PMID 19732867). At least 16 unique variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 11 probands in 6 publications (PMIDs 26969326, 21465660, 19732867). Variants in this gene segregated with disease in 13 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is thought to be that loss of function of the LOXHD1 protein is deleterious to hair cell function (PMID: 19732867). This gene-disease association is supported by animal an animal model that also demonstrated expression of LOXHD1 in the ear (PMID: 19732867). Studies have also identified this gene to be related to dominant late-onset Fuchs corneal dystrophy (PMID: 27121161, 22341973, 23585771). In summary, LOXHD1 is definitively associated with ARNSHL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 77AR

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19732867; 23226338

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LOXHD1 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 2320

Autosomal recessive nonsyndromic hearing loss 77Total: 879

Inborn genetic diseasesTotal: 407

not specifiedTotal: 377

LOXHD1-related disorderTotal: 219

Nonsyndromic genetic hearing lossTotal: 16

Hearing impairmentTotal: 15

Rare genetic deafnessTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001384474.1. 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		1 clinvar	30 clinvar	969 clinvar	7 clinvar	1007
missense		23 clinvar	844 clinvar	68 clinvar	10 clinvar	945
nonsense	74 clinvar	82 clinvar	1 clinvar			157
start loss	1 clinvar		1 clinvar			2
frameshift	112 clinvar	98 clinvar	2 clinvar	1 clinvar		213
splice donor/acceptor (+/-2bp)	14 clinvar	101 clinvar	3 clinvar			118
Total	201	305	881	1038	17	2442

Highest pathogenic variant AF is 0.0010370275

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001384474.1	RefSeq	NP_001371403.1	41	MANE Select
ENST00000642948.1	Ensembl	ENSP00000496347.1	41	MANE Select
NM_001145472.3	RefSeq	NP_001138944.1	22	Standard
NM_001145473.3	RefSeq	NP_001138945.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
oxidation-reduction process
cellular oxidant detoxification

Molecular Function

catalase activity
heme binding

Cellular Component

stereocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300591
Coding exons: 22
Length: 180062
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.38	577	678	0.851	0.0000418	7398
Missense (PolyPhen)		351	432.11	0.8123		4862
Synonymous	1.61	245	279	0.878	0.0000194	2061
Loss of Function	1.47	46	58.1	0.792	0.00000314	621

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in hearing. Required for normal function of hair cells in the inner ear (By similarity). {ECO:0000250, ECO:0000269|PubMed:19732867}.;
Disease: DISEASE: Deafness, autosomal recessive, 77 (DFNB77) [MIM:613079]: A form of non-syndromic deafness characterized by preserved low- frequency hearing, and a trend toward mild to moderate mid- frequency and high-frequency hearing loss during childhood and adolescence. Hearing loss progresses to become moderate to severe at mid and high frequencies during adulthood. {ECO:0000269|PubMed:19732867}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.100

Intolerance Scores

RVIS EVS: 1.18
RVIS percentile EVS: 92.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.868

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High