ClinVar Genomic variation as it relates to human health
NM_005422.4(TECTA):c.5597C>T (p.Thr1866Met)
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(9); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005422.4(TECTA):c.5597C>T (p.Thr1866Met)
Variation ID: 236058 Accession: VCV000236058.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 121168064 (GRCh38) [ NCBI UCSC ] 11: 121038773 (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 Jun 23, 2016 Apr 15, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005422.4:c.5597C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005413.2:p.Thr1866Met missense NM_001378761.1:c.6539C>T NP_001365690.1:p.Thr2180Met missense NC_000011.10:g.121168064C>T NC_000011.9:g.121038773C>T NG_011633.1:g.70399C>T O75443:p.Thr1866Met - Protein change
- T1866M, T2180M
- Other names
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- Canonical SPDI
- NC_000011.10:121168063: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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TBCEL-TECTA | - | - | - | GRCh38 | - | 1030 |
TECTA | - | - |
GRCh38 GRCh37 |
- | 1043 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2022 | RCV000225064.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000264805.7 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000479439.30 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 13, 2016 | RCV000622759.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 21, 2018 | RCV000826186.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2022 | RCV002287396.3 |
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
(Apr 04, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000701182.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 12
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000368224.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TECTA c.5597C>T (p.Thr1866Met) missense variant has been reported in four studies in which it is found in a total of 22 patients with hearing … (more)
The TECTA c.5597C>T (p.Thr1866Met) missense variant has been reported in four studies in which it is found in a total of 22 patients with hearing loss including in three in a homozygous state, in 15 in a heterozygous state and in four patients from the same family in a heterozygous state with another missense variant in cis as part of a complex allele (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011; Moteki et al. 2012). The p.Thr1866Met variant is thought to be the causative variant from the complex allele. The p.Thr1866Met variant showed segregation with disease in a large Korean family, a large Spanish family and a Jewish family (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011). The three individuals in whom the variant was detected in a homozygous state showed a more severe hearing loss than that of their older relatives carrying the variant in a heterozygous state (Hildebrand et al. 2011). The p.Thr1866Met variant was absent from a total of 594 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele in an area of good sequence coverage so the variant is presumed to be rare. The p.Thr1866Met variant is located in the ZP domain of tectorin, which is highly conserved across species; the Thr1866 residue itself is highly conserved. Based on the collective evidence, the p.Thr1866Met variant is classified as pathogenic for autosomal dominant 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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Likely pathogenic
(May 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967729.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Thr1866Met variant in TECTA has been reported in 6 individuals with hearin g loss and segregated in >10 affected family members (Brownstein 2011, Hildebran … (more)
The p.Thr1866Met variant in TECTA has been reported in 6 individuals with hearin g loss and segregated in >10 affected family members (Brownstein 2011, Hildebran d 2011, Mori 2016, Moteki 2012, Sagong 2010, Su 2014, Zazo Seco 2017). In one f amily, several affected individuals were homozygous for the variant and were rep orted to have a more severe hearing loss than the heterozygotes (Hildebrand 2011 ). This variant has also been reported in ClinVar as Pathogenic/Likely Pathogen ic by four other clinical laboratories (Variation ID# 236058). It has been iden tified in 1/111688 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs140236996). Please note that for d iseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population . Computational prediction tools and conservation analysis suggest that the p.Th r1866Met variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is like ly pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Deafness, autosomal dominant 12
Affected status: yes
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251503.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The TECTA c.5597C>T (p.T1866M) variant has been previously reported in at least 3 families with autosomal dominant nonsyndromic hearing loss. This variant affects a well-conserved … (more)
The TECTA c.5597C>T (p.T1866M) variant has been previously reported in at least 3 families with autosomal dominant nonsyndromic hearing loss. This variant affects a well-conserved amino acid located in the ZP domain of the encoded protein (PMID: 20947814; 21520338; 22718023). (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 21
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000368223.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Pathogenic
(Jan 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 12
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368511.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP1_P,PP3.
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 12
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058957.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236058, PS1_S). The variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236058, PS1_S). The variant was co-segregated with Deafness, autosomal dominant 8/12 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 21520338, 21917145) (PP1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.761, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present) , Tinnitus (present)
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Likely pathogenic
(Sep 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sensorineural hearing loss disorder
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002578026.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PS5,PM2,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Sensorineural hearing loss disorder (present)
Age: 20-29 years
Sex: female
Tissue: blood
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Pathogenic
(Nov 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 12
Affected status: yes
Allele origin:
germline
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The Shared Resource Centre "Genome", Research Centre for Medical Genetics
Accession: SCV002756432.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741538.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian/Irish/African American/British/Native American
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian/Irish/African American/British/Native American
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Pathogenic
(Oct 16, 2023)
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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: SCV000568839.6
First in ClinVar: Apr 27, 2017 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24006325, 18022253, 22718023, 25413827, 21917145, 21520338, 23891399, 18797289, 17431902, 12746400, 9590290, 9150164, 30935366, 31163360, 32853555, 28000701, 24586623, 31554319, 27627659, 34795337, 16718611, 34599366, 20947814) (less)
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Pathogenic
(Jan 13, 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: SCV002239480.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1866 of the TECTA protein (p.Thr1866Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1866 of the TECTA protein (p.Thr1866Met). This variant is present in population databases (rs140236996, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 20947814, 31163360, 31554319, 32853555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236058). 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 TECTA protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248731.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 19, 2016)
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no assertion criteria provided
Method: research
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Autosomal dominant nonsyndromic hearing loss 12
Affected status: yes
Allele origin:
germline
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Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV000282008.1
First in ClinVar: Jun 23, 2016 Last updated: Jun 23, 2016
Comment:
NSHL; dominant, DFNA12
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Comment:
Congenital, progressive, moderate-profound HL
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Likely 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: SCV002037533.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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Likely 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: SCV002038330.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 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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Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
The Prevalence and Clinical Characteristics of TECTA-Associated Autosomal Dominant Hearing Loss. | Yasukawa R | Genes | 2019 | PMID: 31554319 |
Genetic testing for congenital non-syndromic sensorineural hearing loss. | Raymond M | International journal of pediatric otorhinolaryngology | 2019 | PMID: 31163360 |
The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands. | Zazo Seco C | European journal of human genetics : EJHG | 2017 | PMID: 28000701 |
Social Health Insurance-Based Simultaneous Screening for 154 Mutations in 19 Deafness Genes Efficiently Identified Causative Mutations in Japanese Hearing Loss Patients. | Mori K | PloS one | 2016 | PMID: 27627659 |
A novel mutation in the TECTA gene in a Chinese family with autosomal dominant nonsyndromic hearing loss. | Su Y | PloS one | 2014 | PMID: 24586623 |
TECTA mutations in Japanese with mid-frequency hearing loss affected by zona pellucida domain protein secretion. | Moteki H | Journal of human genetics | 2012 | PMID: 22718023 |
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. | Brownstein Z | Genome biology | 2011 | PMID: 21917145 |
DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss. | Hildebrand MS | Human mutation | 2011 | PMID: 21520338 |
Two novel missense mutations in the TECTA gene in Korean families with autosomal dominant nonsyndromic hearing loss. | Sagong B | Annals of clinical and laboratory science | 2010 | PMID: 20947814 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TECTA | - | - | - | - |
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Text-mined citations for rs140236996 ...
HelpRecord last updated Apr 15, 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.