in compound heterozygosis with the c.413C>A variant in a subject with bilateral non-syndromic sensorineural postlingual progressive hearing loss (sporadic)
ClinVar Genomic variation as it relates to human health
NM_001256317.3(TMPRSS3):c.346G>A (p.Val116Met)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001256317.3(TMPRSS3):c.346G>A (p.Val116Met)
Variation ID: 432009 Accession: VCV000432009.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 42388503 (GRCh38) [ NCBI UCSC ] 21: 43808612 (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 Aug 20, 2017 Nov 24, 2024 Sep 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001256317.3:c.346G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001243246.1:p.Val116Met missense NM_001256317.1:c.346G>A NM_024022.4:c.346G>A NP_076927.1:p.Val116Met missense NM_032404.3:c.-36G>A 5 prime UTR NM_032405.2:c.346G>A NP_115781.1:p.Val116Met missense NC_000021.9:g.42388503C>T NC_000021.8:g.43808612C>T NG_011629.2:g.12589G>A - Protein change
- V116M
- Other names
- -
- Canonical SPDI
- NC_000021.9:42388502: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| TMPRSS3 | - | - |
GRCh38 GRCh37 |
569 | 671 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2024 | RCV000498701.7 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 23, 2024 | RCV001283845.5 |
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
(-)
|
criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 8
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital
Accession: SCV001792229.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
in compound heterozygosis with the c.413C>A variant in a subject with bilateral non-syndromic sensorineural postlingual progressive hearing loss (sporadic)
Clinical Features:
Postlingual sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
|
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Likely pathogenic
(Jun 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589665.6
First in ClinVar: Aug 20, 2017 Last updated: Jul 23, 2024 |
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26186295, 29072634, 31589614, … (more)
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26186295, 29072634, 31589614, 24416283, 32860223, 34599368, 36871673, 38691166, 34868270, 37331337, 34652575, 38378725) (less)
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Likely pathogenic
(Mar 15, 2022)
|
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: SCV002811716.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003444392.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 116 of the TMPRSS3 protein (p.Val116Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 116 of the TMPRSS3 protein (p.Val116Met). This variant is present in population databases (rs200090033, gnomAD 0.02%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 24416283, 32860223, 34599368). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432009). 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 TMPRSS3 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 23, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 8
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086099.2
First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (68 heterozygotes, 3 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in compound heterozygous and homozygous individuals with hearing loss in the literature (PMID: 29072634, 24416283, 3459936, 32860223, 30919572). (SP) 0906- Segregation evidence for this variant is inconclusive. The variant has segregated in a brother and sister, however this is insufficient for pathogenic evidence (PMID: 24416283). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant in cis with p.(Val291Leu) showed a significantly reduced proteolytic activity in a yeast based protease assay. (PMID: 29072634). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Aug 07, 2020)
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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
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469277.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
Comment:
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26186295, 29072634, 31589614, 24416283, 32860223, 34599368, 36871673, 38691166, 34868270, 37331337, 34652575, 38378725)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 116 of the TMPRSS3 protein (p.Val116Met). This variant is present in population databases (rs200090033, gnomAD 0.02%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 24416283, 32860223, 34599368). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432009). 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 TMPRSS3 protein function. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (68 heterozygotes, 3 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in compound heterozygous and homozygous individuals with hearing loss in the literature (PMID: 29072634, 24416283, 3459936, 32860223, 30919572). (SP) 0906- Segregation evidence for this variant is inconclusive. The variant has segregated in a brother and sister, however this is insufficient for pathogenic evidence (PMID: 24416283). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant in cis with p.(Val291Leu) showed a significantly reduced proteolytic activity in a yeast based protease assay. (PMID: 29072634). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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. |
Comment:
in compound heterozygosis with the c.413C>A variant in a subject with bilateral non-syndromic sensorineural postlingual progressive hearing loss (sporadic)
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26186295, 29072634, 31589614, 24416283, 32860223, 34599368, 36871673, 38691166, 34868270, 37331337, 34652575, 38378725)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 116 of the TMPRSS3 protein (p.Val116Met). This variant is present in population databases (rs200090033, gnomAD 0.02%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 24416283, 32860223, 34599368). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432009). 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 TMPRSS3 protein function. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (68 heterozygotes, 3 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in compound heterozygous and homozygous individuals with hearing loss in the literature (PMID: 29072634, 24416283, 3459936, 32860223, 30919572). (SP) 0906- Segregation evidence for this variant is inconclusive. The variant has segregated in a brother and sister, however this is insufficient for pathogenic evidence (PMID: 24416283). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant in cis with p.(Val291Leu) showed a significantly reduced proteolytic activity in a yeast based protease assay. (PMID: 29072634). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss. | Batissoco AC | Human genetics | 2022 | PMID: 34599368 |
| Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing. | Safka Brozkova D | Clinical genetics | 2020 | PMID: 32860223 |
| Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience. | Al-Dewik N | American journal of medical genetics. Part A | 2019 | PMID: 30919572 |
| The Analysis of A Frequent TMPRSS3 Allele Containing P.V116M and P.V291L in A Cis Configuration among Deaf Koreans. | Kim AR | International journal of molecular sciences | 2017 | PMID: 29072634 |
| Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE. | Ganapathy A | PloS one | 2014 | PMID: 24416283 |
| [Local radiotherapy combined with systemic chemotherapy in 3 children with osteosarcoma of an extremity]. | Kühl J | Klinische Padiatrie | 1986 | PMID: 3459936 |
Text-mined citations for rs200090033 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.