ClinVar Genomic variation as it relates to human health
NM_024334.3(TMEM43):c.1114C>T (p.Arg372Ter)
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.
Likely pathogenic(1); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024334.3(TMEM43):c.1114C>T (p.Arg372Ter)
Variation ID: 403555 Accession: VCV000403555.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 14141706 (GRCh38) [ NCBI UCSC ] 3: 14183206 (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 Apr 9, 2017 May 1, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024334.3:c.1114C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077310.1:p.Arg372Ter nonsense NC_000003.12:g.14141706C>T NC_000003.11:g.14183206C>T NG_008975.1:g.21767C>T LRG_435:g.21767C>T LRG_435t1:c.1114C>T LRG_435p1:p.Arg372Ter - Protein change
- R372*
- Other names
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- Canonical SPDI
- NC_000003.12:14141705: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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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TMEM43 | No evidence available | No evidence available |
GRCh38 GRCh37 |
943 | 986 |
Conditions - Germline
Condition
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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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2016 | RCV000455923.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV001346107.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV001524277.3 | |
Likely pathogenic (3) |
criteria provided, single submitter
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Feb 23, 2023 | RCV002221536.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 20, 2021 | RCV002223838.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 23, 2021 | RCV002436372.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 16, 2021 | RCV002481361.1 |
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
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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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Uncertain significance
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540548.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a stop variant in exon 12 of 12 in TMEM43. This variant has not been reported in affected individuals and is not present in ClinVar. It has a Max MAF of 0.001% in ExAC (1 allele) and 0.006% in gnomAD (1 allele). This variant is predicted to be pathogenic by prediction tools. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Sep 20, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502372.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Aug 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 5
Emery-Dreifuss muscular dystrophy 7, autosomal dominant Auditory neuropathy, autosomal dominant 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002775507.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Auditory neuropathy, autosomal dominant 3
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841752.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 34050020). The variant has been reported to be associated with TMEM43 related disorder (ClinVar ID: VCV000403555 / PMID: 34050020). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
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Uncertain significance
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 5
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001540282.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg372*) in the TMEM43 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg372*) in the TMEM43 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the TMEM43 protein. This variant is present in population databases (rs773224617, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with auditory neuropathy (PMID: 34050020). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 403555). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TMEM43 function (PMID: 34050020). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001734079.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal in the last exon. This variant is … (more)
This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncation protein. A functional study using a knock-in mouse model has shown that this variant results in progressive hearing loss without signs of arrhythmogenic cardiomyopathy (PMID: 34050020). This variant has been reported in two families affected with adult-onset autosomal dominant auditory neuropathy spectrum disorder. Affected carriers from these families did not display symptoms of arrhythmia or other heart abnormalities (PMID: 34050020). This variant has been identified in 2/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 5
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004841613.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal. This variant is expected to escape nonsense-mediated … (more)
This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal. This variant is expected to escape nonsense-mediated decay and be expressed as a truncation protein. A functional study has shown that this variant causes progressive hearing loss in knock-in mouse which does not show any sign of arrhythmogenic right ventricular cardiomyopathy in the electrocardiography (Jang et al. 2020, doi: https://doi.org/10.1101/2020.07.27.222323). This variant has been reported in two families affected with adult-onset autosomal dominant auditory neuropathy spectrum disorder. Affected carriers from these families did not display symptoms of either arrhythmia or any other heart abnormalities (Jang et al. 2020, doi: https://doi.org/10.1101/2020.07.27.222323). This variant has been identified in 2/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with auditory neuropathy spectrum disorder, but the available evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for cardiomyopathy. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002748233.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R372* variant (also known as c.1114C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide … (more)
The p.R372* variant (also known as c.1114C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide position 1114. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TMEM43 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear (less)
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Pathogenic
(Jul 13, 2023)
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no assertion criteria provided
Method: literature only
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AUDITORY NEUROPATHY, AUTOSOMAL DOMINANT 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002498731.2
First in ClinVar: Apr 12, 2022 Last updated: Jul 16, 2023 |
Comment on evidence:
In 15 individuals from 2 unrelated families, a Han Chinese family (HN66) and a Korean family (SB162), with autosomal dominant auditory neuropathy-3 (AUNA3; 619832), Jang … (more)
In 15 individuals from 2 unrelated families, a Han Chinese family (HN66) and a Korean family (SB162), with autosomal dominant auditory neuropathy-3 (AUNA3; 619832), Jang et al. (2021) identified a heterozygous c.1114C-T transition (c.1114C-T, NM_024334) in the TMEM43 gene, resulting in an arg372-to-ter (R372X) substitution. The mutation was found by a combination of linkage analysis, whole-exome sequencing, and Sanger sequencing. Transfection of HEK293 cells with TMEM43 with the R372X mutation resulted in decreased TMEM43 protein content, possibly due to decreased protein stability. Mouse models that were heterozygous or homozygous for the R372X mutation in the TMEM43 gene demonstrated progressive hearing loss and abnormal passive conductance current from glia-like supporting cells in the organ of Corti of the inner ear. (less)
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Likely pathogenic
(Sep 22, 2022)
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no assertion criteria provided
Method: clinical testing
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Auditory neuropathy, autosomal dominant 3
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV004167603.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
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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 nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. | Jang MW | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34050020 |
Text-mined citations for rs773224617 ...
HelpRecord last updated May 01, 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.