ClinVar Genomic variation as it relates to human health
NM_004700.4(KCNQ4):c.827G>C (p.Trp276Ser)
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_004700.4(KCNQ4):c.827G>C (p.Trp276Ser)
Variation ID: 6242 Accession: VCV000006242.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40819465 (GRCh38) [ NCBI UCSC ] 1: 41285137 (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 4, 2013 Oct 1, 2022 Jun 24, 2014 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004700.4:c.827G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004691.2:p.Trp276Ser missense NM_172163.3:c.827G>C NP_751895.1:p.Trp276Ser missense NC_000001.11:g.40819465G>C NC_000001.10:g.41285137G>C NG_008139.3:g.40679G>C LRG_1378:g.40679G>C LRG_1378t1:c.827G>C LRG_1378p1:p.Trp276Ser P56696:p.Trp276Ser - Protein change
- W276S
- Other names
- -
- Canonical SPDI
- NC_000001.11:40819464:G:C
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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) 0.00001
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
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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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KCNQ4 | - | - |
GRCh38 GRCh37 |
353 | 373 |
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
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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 (2) |
no assertion criteria provided
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Jul 1, 2002 | RCV000006620.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 24, 2014 | RCV000211784.4 | |
Pathogenic (2) |
no assertion criteria provided
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- | RCV001723546.3 |
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
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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
(Jun 24, 2014)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000206332.4
First in ClinVar: Jan 31, 2015 Last updated: Jun 01, 2016 |
Comment:
The Trp276Ser variant in KCNQ4 has been reported in 3 Dutch and 1 Japanese famil ies with autosomal dominant hearing loss, segregated with the disease … (more)
The Trp276Ser variant in KCNQ4 has been reported in 3 Dutch and 1 Japanese famil ies with autosomal dominant hearing loss, segregated with the disease in over 30 affected relatives (Coucke 1999, Van Camp 2002, Topsakal 2005, Akita 2001), and was absent from large population studies. Additionally, in vitro functional stu dies indicate that the Trp276Ser variant disrupts normal potassium channel funct ion (Baek 2011, Kim 2011, Gao 2013). In summary, the Trp237Ser variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/ lmm) based upon segregation studies, absence from controls, and functional evide nce. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 01, 2002)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL DOMINANT 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026803.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 24, 2019 |
Comment on evidence:
In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified an 827G-C transversion in exon 5 of the KCNQ4 gene … (more)
In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified an 827G-C transversion in exon 5 of the KCNQ4 gene resulting in a trp276-to-ser (W276S) mutation in the pore region of the protein. Akita et al. (2001) found this mutation in a Japanese family with deafness in 4 successive generations. Van Camp et al. (2002) described 2 additional families originating from Europe and Japan with the W276S mutation. They compared the disease-associated haplotype of the 3 W276S-bearing families using closely linked microsatellite markers and intragenic SNPS. Van Camp et al. (2002) found differences between the haplotypes, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred 3 times independently, and most likely represents a hotspot for a mutation in the KCNQ4 gene. (less)
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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: SCV001954349.1 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: SCV001965805.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal dominant nonsyndromic hearing loss 2A
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041114.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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DFNA2 Nonsyndromic Hearing Loss. | Adam MP | - | 2018 | PMID: 20301388 |
Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. | Gao Y | Journal of cellular and molecular medicine | 2013 | PMID: 23750663 |
Simultaneous screening of multiple mutations by invader assay improves molecular diagnosis of hereditary hearing loss: a multicenter study. | Usami S | PloS one | 2012 | PMID: 22384008 |
Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. | Kim HJ | The Journal of biological chemistry | 2011 | PMID: 20966080 |
Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology. | Baek JI | Biochimica et biophysica acta | 2011 | PMID: 20832469 |
Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S). | Topsakal V | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2005 | PMID: 15699719 |
A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. | Van Camp G | Human mutation | 2002 | PMID: 12112653 |
Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. | De Leenheer EM | The Annals of otology, rhinology, and laryngology | 2002 | PMID: 11915881 |
Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. | Akita J | Journal of human genetics | 2001 | PMID: 11450843 |
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. | Coucke PJ | Human molecular genetics | 1999 | PMID: 10369879 |
Linkage of autosomal dominant hearing loss to the short arm of chromosome 1 in two families. | Coucke P | The New England journal of medicine | 1994 | PMID: 8035838 |
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Text-mined citations for rs80358277 ...
HelpRecord last updated Dec 25, 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.