TMC1

protein-coding

transmembrane channel like 1, the group of Transmembrane channel like family

Gene summary

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]

Previous symbols:

DFNA36
DFNB7
DFNB11

MANE transcript

NM_138691.3

Inheritance

AD, SD, AR

ClinVar variants

P:206U:262B:178

Top phenotype

Deafness, autosomal recessive 7

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr9:72,521,608-72,838,297

External References & Databases

Ensembl (ENSG00000165091)

Transcript & Mutation Effects

hg38 • Region Span ~316.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The TMC1 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 11/3/2017. This association was made using case-level data and experimental data. At least 7 missense variants have been reported in humans. TMC1 was first associated with this disease in humans as early as 2002 (Kimura et al.). Association is seen in at least 9 probands in 8 publications (26079994, 19180119, 17250663, 11850618, 26346818, 20447146, 24827932, 25560804). Variants in this gene segregated with disease in >50 additional family members. The mechanism for disease is hypothesized to be that TMC1 and TMC2 are required for mechanoelectrical transmission in cochlear and vestibular hair cells. This gene-disease association is supported by animal models, functional alteration of mechanoelectrical transduction in mouse OHC's, expression studies as well as a rescue in a mouse model. In summary, TMC1 is definitively associated with autosomal dominant nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 6/22/2018.

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0019497

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010967

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010967

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 36STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011708

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 36STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011708

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010967

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 36MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011708

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 7AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 11850618; 17250663; 18616530; 23226338; 24827932; 34523024

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMC1 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 623

Autosomal recessive nonsyndromic hearing loss 7Total: 172

not specifiedTotal: 96

Inborn genetic diseasesTotal: 89

TMC1-related disorderTotal: 85

Autosomal dominant nonsyndromic hearing loss 36Total: 78

Hearing loss, autosomal recessiveTotal: 18

Rare genetic deafnessTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138691.3. 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			7 clinvar	166 clinvar		173
missense	15 clinvar	49 clinvar	250 clinvar	11 clinvar	1 clinvar	326
nonsense	30 clinvar	17 clinvar	2 clinvar			49
start loss						0
frameshift	34 clinvar	17 clinvar	1 clinvar			52
splice donor/acceptor (+/-2bp)	22 clinvar	22 clinvar	2 clinvar			46
Total	101	105	262	177	1	646

Highest pathogenic variant AF is 0.00075989444

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138691.3	RefSeq	NP_619636.2	20	MANE Select
ENST00000297784.10	Ensembl	ENSP00000297784.6	20	MANE Select
ENST00000340019.4	Ensembl	ENSP00000341433.3	20	Standard
ENST00000340019.5	Ensembl	ENSP00000341433.3	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

detection of mechanical stimulus involved in sensory perception of sound
vestibular reflex
auditory receptor cell development
calcium ion transmembrane transport
regulation of calcium ion transmembrane transport

Molecular Function

ion channel activity
voltage-gated calcium channel activity
mechanosensitive ion channel activity

Cellular Component

integral component of plasma membrane
external side of plasma membrane
stereocilium tip

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297784
Coding exons: 20
Length: 314551
Individuals with no LoFs: 125549
Homozygous LoFs: 0
Heterozygous LoFs: 199
Defined: 125748
p: 0.000792

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.858	350	398	0.879	0.0000208	5063
Missense (PolyPhen)		106	129.51	0.81846		1717
Synonymous	-0.256	146	142	1.03	0.00000813	1353
Loss of Function	1.69	35	47.6	0.736	0.00000265	552

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00055	0.00054	rare
Finnish	0.0033	0.0033	notable
European (Non-Finnish)	0.00064	0.00063	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable ion channel required for the normal function of cochlear hair cells. {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 7 (DFNB7) [MIM:600974]: 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:11850618}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.171

Intolerance Scores

LoFtool: 0.819
RVIS EVS: -0.64
RVIS percentile EVS: 16.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.209

Gene Damage Prediction

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