ClinVar Genomic variation as it relates to human health
NM_138691.3(TMC1):c.1763+3A>G
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.
Pathogenic(5); Likely pathogenic(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138691.3(TMC1):c.1763+3A>G
Variation ID: 47864 Accession: VCV000047864.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.13 9: 72816213 (GRCh38) [ NCBI UCSC ] 9: 75431129 (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 Dec 6, 2016 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138691.3:c.1763+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000009.12:g.72816213A>G NC_000009.11:g.75431129A>G NG_008213.1:g.299413A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000009.12:72816212:A:G
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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 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00044
The Genome Aggregation Database (gnomAD) 0.00056
The Genome Aggregation Database (gnomAD), exomes 0.00061
Exome Aggregation Consortium (ExAC) 0.00080
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
713 | - |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (1) |
criteria provided, single submitter
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Apr 11, 2017 | RCV000041134.7 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000293958.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000357976.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2017 | RCV000760983.5 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001542674.2 |
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
Help
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
(Jun 21, 2017)
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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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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000890894.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 11, 2017)
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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: SCV000064825.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The c.1763+3A>G variant in TMC1 has been previously reported in the homozygous s tate in one individual and in the compound heterozygous state in five … (more)
The c.1763+3A>G variant in TMC1 has been previously reported in the homozygous s tate in one individual and in the compound heterozygous state in five other indi viduals with hearing loss, and segregated in five affected family members (de He er 2011, Schrauwen 2013, LMM data). It has been identified in 0.1% (153/152370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs370898981). This variant is located in the 5' spli ce region, and RT-PCR analysis of RNA from affected individuals reveals abnormal splicing of TMC1 transcripts resulting in a premature stop codon (de Heer 2011) . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive nonsyndromic sensorineural hearing loss. ACMG/AMP Criteria appl ied: PM3_VeryStrong, PP1_Strong, PS3. (less)
Number of individuals with the variant: 16
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Pathogenic
(Nov 01, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002018979.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic Hearing Loss, Dominant
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000480643.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 7
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000480644.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TMC1 c.1763+3A>G splice region variant was first reported by de Heer et al. (2011) in a homozygous state in three siblings from a large, … (more)
The TMC1 c.1763+3A>G splice region variant was first reported by de Heer et al. (2011) in a homozygous state in three siblings from a large, distantly-consanguineous Dutch family affected with autosomal recessive nonsyndromic hearing loss. Both unaffected parents were heterozygous for this variant. The c.1763+3A>G variant was subsequently identified in a compound heterozygous state with a nonsense variant in a patient of European ethnicity (Schrauwen et al. 2013). The variant was found in a heterozygous state in one of 177 Dutch control individuals and is reported at a frequency of 0.00130 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis on RNA isolated from blood of a homozygous patient revealed that the c.1763+3A>G variant causes alternative splicing and introduces 47 bp of intronic sequence into exon 19, which ultimately results in a frameshift and premature stop. Minigene analysis revealed that the variant completely abolished the normal splicing signal (de Heer et al. 2011). Based on the evidence, the p.1763+3A>G variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 27, 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: SCV000330030.9
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function; aberrant splicing results in a 47 base pair extension of exon 19, causing a frameshift, leading … (more)
Non-canonical splice site variant demonstrated to result in loss-of-function; aberrant splicing results in a 47 base pair extension of exon 19, causing a frameshift, leading to a premature stop codon in exon 20 and the incorporation of 81 aberrant amino acids in the protein (de Heer et al., 2011); This variant is associated with the following publications: (PMID: 31980526, 33352559, 24933710, 34758253, 23208854, 21252500, 31152317) (less)
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Pathogenic
(Jan 18, 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: SCV003300394.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 19 of the TMC1 gene. It does not directly change the encoded amino acid sequence of the TMC1 protein. … (more)
This sequence change falls in intron 19 of the TMC1 gene. It does not directly change the encoded amino acid sequence of the TMC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370898981, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 21252500). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 47864). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site resulting in the addition of 47 nucleotides from the intron and a subsequent frameshift and introduces a premature termination codon (PMID: 21252500). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 36
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760241.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969920.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956099.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing. | Schrauwen I | American journal of medical genetics. Part A | 2013 | PMID: 23208854 |
Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1. | de Heer AM | Audiology & neuro-otology | 2011 | PMID: 21252500 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs370898981 ...
HelpRecord last updated Mar 17, 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.