ClinVar Genomic variation as it relates to human health
NM_138691.3(TMC1):c.2144A>T (p.Tyr715Phe)
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.2144A>T (p.Tyr715Phe)
Variation ID: 47868 Accession: VCV000047868.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.13 9: 72830465 (GRCh38) [ NCBI UCSC ] 9: 75445381 (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, 2018 Mar 4, 2023 Oct 17, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138691.3:c.2144A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619636.2:p.Tyr715Phe missense NC_000009.12:g.72830465A>T NC_000009.11:g.75445381A>T NG_008213.1:g.313665A>T - Protein change
- Y715F
- Other names
- -
- Canonical SPDI
- NC_000009.12:72830464:A: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00036
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
The Genome Aggregation Database (gnomAD) 0.00057
Trans-Omics for Precision Medicine (TOPMed) 0.00070
Exome Aggregation Consortium (ExAC) 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00057
The Genome Aggregation Database (gnomAD) 0.00070
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 |
715 | 758 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2016 | RCV000041138.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001169137.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001169138.4 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2022 | RCV001723626.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 27, 2021 | RCV002490577.1 |
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
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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Uncertain significance
(Dec 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000064829.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Tyr715Phe variant in TMC1 has been identified by our laboratory in the het erozygous state in 2 siblings with hearing loss in a Caucasian … (more)
The p.Tyr715Phe variant in TMC1 has been identified by our laboratory in the het erozygous state in 2 siblings with hearing loss in a Caucasian family. This vari ant has been identified in 31/65906 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41310067). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Tyr715Phe variant is uncertain. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 36
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001331783.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 12, 2018)
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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: SCV001331784.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Nov 17, 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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GeneDx
Accession: SCV002028932.2
First in ClinVar: Dec 04, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Dec 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 7
Autosomal dominant nonsyndromic hearing loss 36
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776150.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 17, 2022)
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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: SCV003265456.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 715 of the TMC1 protein (p.Tyr715Phe). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 715 of the TMC1 protein (p.Tyr715Phe). This variant is present in population databases (rs41310067, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with TMC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 47868). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMC1 protein function. 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
(-)
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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: SCV001958079.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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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: SCV001972242.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs41310067 ...
HelpRecord last updated Apr 09, 2023
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.