ClinVar Genomic variation as it relates to human health
NM_004700.4(KCNQ4):c.842T>C (p.Leu281Ser)
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.842T>C (p.Leu281Ser)
Variation ID: 6246 Accession: VCV000006246.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40819882 (GRCh38) [ NCBI UCSC ] 1: 41285554 (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 Feb 14, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004700.4:c.842T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004691.2:p.Leu281Ser missense NM_172163.3:c.842T>C NP_751895.1:p.Leu281Ser missense NC_000001.11:g.40819882T>C NC_000001.10:g.41285554T>C NG_008139.3:g.41096T>C LRG_1378:g.41096T>C LRG_1378t1:c.842T>C LRG_1378p1:p.Leu281Ser P56696:p.Leu281Ser - Protein change
- L281S
- Other names
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- Canonical SPDI
- NC_000001.11:40819881:T: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
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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
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
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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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KCNQ4 | - | - |
GRCh38 GRCh37 |
358 | 378 |
Conditions - Germline
Condition
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000006624.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2022 | RCV001567939.5 |
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
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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
(Jan 17, 2020)
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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: SCV001791714.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Published functional studies demonstrate the L281S mutation leads to non-functional channels and improper trafficking of mutant channels to the cell surface with a dominant negative … (more)
Published functional studies demonstrate the L281S mutation leads to non-functional channels and improper trafficking of mutant channels to the cell surface with a dominant negative effect on WT channels (Kim et al., 2011; Gao et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10571947, 23776385, 18797286, 12408061, 26036578, 24616153, 11252765, 28802383, 25116015, 23399560, 21951272, 17033161, 23750663, 20966080, 22785243) (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 2A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004173231.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Aug 09, 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: SCV003523271.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 6246). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10571947). It … (more)
ClinVar contains an entry for this variant (Variation ID: 6246). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10571947). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the KCNQ4 protein (p.Leu281Ser). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ4 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 23750663). (less)
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Pathogenic
(Dec 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal dominant 2A
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448747.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jan 14, 2011)
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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: SCV000026807.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 5-generation American family of Austrian origin in which 51 members had nonsyndromic dominant progressive hearing loss linked to the DFNA2A (600101) locus on … (more)
In a 5-generation American family of Austrian origin in which 51 members had nonsyndromic dominant progressive hearing loss linked to the DFNA2A (600101) locus on 1p34, Talebizadeh et al. (1999) identified an 824T-C transition in the KCNQ4 gene, resulting in a leu281-to-ser (L281S) substitution. The mutation occurred in the pore region of the protein (Kim et al., 2011). (less)
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Pathogenic
(Aug 20, 2015)
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no assertion criteria provided
Method: literature only
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Autosomal dominant nonsyndromic hearing loss 2A
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000777818.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Comment:
This variant used to be reported in GeneReviews NBK1209.
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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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A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss. | Wasano K | Biochemical and biophysical research communications | 2015 | PMID: 26036578 |
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 |
Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. | Kim HJ | The Journal of biological chemistry | 2011 | PMID: 20966080 |
Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. | Talebizadeh Z | Human mutation | 1999 | PMID: 10571947 |
Text-mined citations for rs80358278 ...
HelpRecord last updated Feb 14, 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.