ClinVar Genomic variation as it relates to human health
NM_001256317.3(TMPRSS3):c.208del (p.His70fs)
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_001256317.3(TMPRSS3):c.208del (p.His70fs)
Variation ID: 165492 Accession: VCV000165492.36
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 42389043 (GRCh38) [ NCBI UCSC ] 21: 43809152 (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 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001256317.3:c.208del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001243246.1:p.His70fs frameshift NM_024022.2:c.208del NM_024022.3:c.208delC NM_024022.4:c.208del NP_076927.1:p.His70fs frameshift NM_032404.3:c.-174del 5 prime UTR NM_032405.2:c.208del NP_115781.1:p.His70fs frameshift NC_000021.9:g.42389044del NC_000021.8:g.43809153del NG_011629.2:g.12049del - Protein change
- H70fs
- Other names
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- Canonical SPDI
- NC_000021.9:42389042:GG: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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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TMPRSS3 | - | - |
GRCh38 GRCh37 |
554 | 653 |
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 (1) |
criteria provided, single submitter
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Mar 20, 2017 | RCV000152065.6 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000412773.10 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2022 | RCV000371920.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 27, 2017 | RCV000623444.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2021 | RCV001375379.2 |
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
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 8
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000436178.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TMPRSS3 c.208delC (p.His70ThrfsTer19) variant has been reported in at least six studies and is found in a total of at least 27 individuals with … (more)
The TMPRSS3 c.208delC (p.His70ThrfsTer19) variant has been reported in at least six studies and is found in a total of at least 27 individuals with nonsyndromic hearing loss, including 24 in a homozygous state and three in a compound heterozygous state (Wattenhofer et al. 2002; Ahmed et al. 2004; Kecmanovic et al. 2009; Weegerink et al. 2011; Lee et al. 2012; Battelino et al. 2015). The variant segregated with disease in at least three unrelated families. The p.His70ThrfsTer19 variant was absent from 700 control alleles but is reported at a frequency of 0.00074 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.His70ThrfsTer19 variant results in a frameshift, and is predicted to result in premature termination of the protein. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.His70ThrfsTer19 variant is classified as 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
(Mar 20, 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: SCV000200697.5
First in ClinVar: Feb 02, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.His70fs variant in TMPRSS3 has been reported in the homozygous or compound heterozygous state in more than 10 probands with nonsyndromic hearing loss and … (more)
The p.His70fs variant in TMPRSS3 has been reported in the homozygous or compound heterozygous state in more than 10 probands with nonsyndromic hearing loss and has segregated in more than 10 affected family members (Wattenhofer 2002, Ahmed 2004, Kecmanovic 2008, Weegerink 2011, Lee 2011, Battelino 2016, LMM data). It h as been identified in 0.1% (10/10144) of Ashkenazi Jewish chromosomes and 0.08% (101/126652) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; rs727503493); however, this frequency is low enough to be consistent with a recessive carrier frequency for hearing loss. Thi s variant is predicted to cause a frameshift, which alters the protein's amino a cid sequence beginning at codon 70 and leads to a premature stop codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, this variant meets criteria to be classified as pathog enic for autosomal recessive hearing loss based on previous reports of biallelic states in affected individuals, segregation studies, and predicted impact to th e protein. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong. (less)
Number of individuals with the variant: 20
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Deafness, autosomal recessive 8
Affected status: yes
Allele origin:
inherited
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251529.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
TMPRSS3 c.208delC (p.H70Tfs) is a frameshift variant that is predicted to result in a nonfunctional protein. This variant has been reported previously in the homozygous … (more)
TMPRSS3 c.208delC (p.H70Tfs) is a frameshift variant that is predicted to result in a nonfunctional protein. This variant has been reported previously in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive nonsyndromic hearing loss (PMID: 11907649, 21534946, 21786053; 26036852). (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 03, 2019)
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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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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449025.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Aug 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 8
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366892.2
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: PVS1,PS1,PM2.
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Likely pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571764.2
First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021 |
Comment:
PVS1_Strong, PM2_Supporting, PM5_Moderate
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Pathogenic
(Nov 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 8
Affected status: yes
Allele origin:
germline
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The Shared Resource Centre "Genome", Research Centre for Medical Genetics
Accession: SCV002756436.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 8
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776345.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 27, 2017)
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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: SCV000742260.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Arthrogryposis multiplex congenita (present) , Clonus (present) , Tremor (present) , Limb hypertonia (present) , Seizures (present) , Apical muscular ventricular septal defect (present) , … (more)
Arthrogryposis multiplex congenita (present) , Clonus (present) , Tremor (present) , Limb hypertonia (present) , Seizures (present) , Apical muscular ventricular septal defect (present) , Atrial septal defect (present) , Hip dislocation (present) , Hip subluxation (present) , Hydronephrosis (present) , Microretrognathia (present) , Gastroesophageal reflux (present) , Aplasia/Hypoplasia of the mandible (present) , Flexion contracture (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Apr 25, 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: SCV000491099.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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)
Frameshift 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: 15447792, 27573290, 19170735, 21534946, 11907649, 21786053, 26036852, 28566687, 29293505, 31270413, 31980526, 31412945, 34171171, 31589614, 32853555, 32860223) (less)
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Pathogenic
(Jan 29, 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: SCV002174397.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.His70Thrfs*19) in the TMPRSS3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.His70Thrfs*19) in the TMPRSS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS3 are known to be pathogenic (PMID: 16021470, 26969326). This variant is present in population databases (rs727503493, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 11907649, 28566687, 29293505). This variant is also known as 207delC. ClinVar contains an entry for this variant (Variation ID: 165492). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2002)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 8
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044740.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2015 |
Comment on evidence:
In a Greek patient with prelingual nonsyndromic sensorineural deafness (DFNB8; 601072), Wattenhofer et al. (2002) identified compound heterozygosity for 2 mutations in exon 4 of … (more)
In a Greek patient with prelingual nonsyndromic sensorineural deafness (DFNB8; 601072), Wattenhofer et al. (2002) identified compound heterozygosity for 2 mutations in exon 4 of the TMPRSS3 gene: a 1-bp deletion (207delC) resulting in a frameshift and a 308A-G transition resulting in an asp103-to-gly (D103G) substitution (605511.0007) in the LDLRA domain. In a Spanish patient with prelingual nonsyndromic sensorineural deafness, Wattenhofer et al. (2002) identified homozygosity for the 207delC mutation. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 8
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760470.1
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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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: SCV001952661.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001965067.1 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
HelpTitle | Author | Journal | Year | Link |
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Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss. | Likar T | PloS one | 2018 | PMID: 29293505 |
Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen. | Lechowicz U | Scientific reports | 2017 | PMID: 28566687 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Pathogenic p.Cys194Metfs*17 variant argues against TMPRSS3/GJB2 digenic inheritance of hearing loss. | Lechowicz U | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2016 | PMID: 26408194 |
TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss. | Battelino S | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2016 | PMID: 26036852 |
Novel TMPRSS3 variants in Pakistani families with autosomal recessive non-syndromic hearing impairment. | Lee K | Clinical genetics | 2012 | PMID: 21534946 |
Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations. | Weegerink NJ | Journal of the Association for Research in Otolaryngology : JARO | 2011 | PMID: 21786053 |
Coexistence of Unverricht-Lundborg disease and congenital deafness: molecular resolution of a complex comorbidity. | Kecmanović M | Epilepsia | 2009 | PMID: 19170735 |
Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population. | Walsh T | Human genomics | 2006 | PMID: 16460646 |
A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. | Wattenhofer M | Human genetics | 2005 | PMID: 16021470 |
Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan. | Ahmed ZM | BMC medical genetics | 2004 | PMID: 15447792 |
Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. | Wattenhofer M | Journal of molecular medicine (Berlin, Germany) | 2002 | PMID: 11907649 |
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Text-mined citations for rs727503493 ...
HelpRecord last updated Feb 20, 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.