ClinVar Genomic variation as it relates to human health
NM_138691.3(TMC1):c.100C>T (p.Arg34Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138691.3(TMC1):c.100C>T (p.Arg34Ter)
Variation ID: 4103 Accession: VCV000004103.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.13 9: 72694578 (GRCh38) [ NCBI UCSC ] 9: 75309494 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 5, 2015 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138691.3:c.100C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619636.2:p.Arg34Ter nonsense NC_000009.12:g.72694578C>T NC_000009.11:g.75309494C>T NG_008213.1:g.177778C>T - Protein change
- R34*
- Other names
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- Canonical SPDI
- NC_000009.12:72694577:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TMC1 | - | - |
GRCh38 GRCh37 |
716 | 759 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000004319.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 13, 2012 | RCV000211859.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000756783.17 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001291357.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 17, 2024 | RCV003987310.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 13, 2012)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000064814.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Arg34X variant in TMC1 has been reported in more than 23 probands with sen sorineural hearing loss (Kurima 2002, Ben Said 2010, Sirmaci 2009, … (more)
The p.Arg34X variant in TMC1 has been reported in more than 23 probands with sen sorineural hearing loss (Kurima 2002, Ben Said 2010, Sirmaci 2009, Kitajiri 2007 , Shafique 2014). Most of these probands, as well as their affected relatives, w ere homozygous for the variant. The p.Arg34X variant has also been identified in 4/15682 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs121908073). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Animal models in mice have shown that loss of TM C1 function causes an auditory phenotype (Kurima 2002). This nonsense variant le ads to a premature termination codon at position 34, which is predicted to lead to a truncated or absent protein. In summary, the p.Arg34X variant meets our cri teria to be classified as pathogenic for hearing loss in an autosomal recessive manner. (less)
Number of individuals with the variant: 7
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058633.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004103, PMID:11850618, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000056, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present) , Progressive visual loss (present)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002218316.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg34*) in the TMC1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg34*) in the TMC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). This variant is present in population databases (rs121908073, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 11850618, 17877751, 31854501). ClinVar contains an entry for this variant (Variation ID: 4103). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884693.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The p.Arg34Ter variant is the most frequently reported pathogenic variant of TMC1 and is likely a founder variant in North African and Middle Eastern populations … (more)
The p.Arg34Ter variant is the most frequently reported pathogenic variant of TMC1 and is likely a founder variant in North African and Middle Eastern populations (Kurima 2002, Ben Said 2010, Shafique 2014, and Dallol 2016). The c.100C>T variant creates a premature termination codon in exon 7 and is predicted to result in a truncated or absent protein product. Based on these observations the p.Arg34Ter variant has been classified pathogenic. (less)
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Pathogenic
(Feb 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522010.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Aug 01, 2020)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
germline
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King Laboratory, University of Washington
Accession: SCV002059893.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
TMC1 c.100C>T, p.R34* is homozygous in 3 Palestinian children with profound pre-lingual hearing loss It was found also in 2 Palestinian children with hearing loss … (more)
TMC1 c.100C>T, p.R34* is homozygous in 3 Palestinian children with profound pre-lingual hearing loss It was found also in 2 Palestinian children with hearing loss in compound heterozygosity with TMC1 c.1532C>A. The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. (less)
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Pathogenic
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000890354.3
First in ClinVar: Mar 19, 2019 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 17877751, 27766948, 24949729, 11850618, 29048421, 20373850, 19187973, 31854501, 31541171, 34426522, 32802042, 32747562, 31589614) (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Autosomal dominant nonsyndromic hearing loss 36
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804963.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Oct 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Deafness, autosomal recessive 7
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV000223953.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Dec 01, 2007)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024490.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 03, 2017 |
Comment on evidence:
In 5 different families from Pakistan, Kurima et al. (2002) found that members with autosomal recessive nonsyndromic neurosensory deafness (DFNB7; 600974) had a 100C-T transition … (more)
In 5 different families from Pakistan, Kurima et al. (2002) found that members with autosomal recessive nonsyndromic neurosensory deafness (DFNB7; 600974) had a 100C-T transition in the TMC1 gene, resulting in an arg34-to-ter (R34X) nonsense mutation. Comparison of linked haplotypes in these families with those in Pakistani individuals with normal hearing confirmed a specific association of R34X with a single identical haplotype. Thus, the R34X mutation in these apparently unrelated families was probably derived from a common founder. The mutation was homozygous in these cases. Kitajiri et al. (2007) identified the R34X mutation in 5 consanguineous Pakistani families with DFNB7. Combined with the results of the report by (Kurima et al., 2002), Kitajiri et al. (2007) estimated that the R34X accounted for 1.8% of deafness in Pakistan. Haplotype analysis indicated a founder effect. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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non-syndromic autosomal recessive hearing loss
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479831.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927953.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Pathogenic
(Jun 04, 2016)
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no assertion criteria provided
Method: research
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
germline
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Hereditary Research Laboratory, Bethlehem University
Accession: SCV000538122.1
First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
FA3 moderate HL at 6y; FA4 profound at 18m
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Pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902388.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 2
Clinical Features:
hearing loss (present)
Family history: yes
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population. | Ramzan K | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2020 | PMID: 31854501 |
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. | Richard EM | Human mutation | 2019 | PMID: 30303587 |
Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families. | Shafique S | PloS one | 2014 | PMID: 24949729 |
Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. | Kawashima Y | The Journal of clinical investigation | 2011 | PMID: 22105175 |
High frequency of the p.R34X mutation in the TMC1 gene associated with nonsyndromic hearing loss is due to founder effects. | Ben Saïd M | Genetic testing and molecular biomarkers | 2010 | PMID: 20373850 |
Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: a report of five novel mutations. | Sirmaci A | International journal of pediatric otorhinolaryngology | 2009 | PMID: 19187973 |
Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan. | Kitajiri SI | Clinical genetics | 2007 | PMID: 17877751 |
Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. | Kurima K | Nature genetics | 2002 | PMID: 11850618 |
Text-mined citations for rs121908073 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.