ClinVar Genomic variation as it relates to human health
NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)
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.803CCT[1] (p.Ser269del)
Variation ID: 208366 Accession: VCV000208366.12
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 1p34.2 1: 40819439-40819441 (GRCh38) [ NCBI UCSC ] 1: 41285111-41285113 (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 27, 2017 Feb 14, 2024 Jun 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004700.4(KCNQ4):c.803_805CCT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
inframe deletion NM_004700.4:c.803CCT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004691.2:p.Ser269del inframe deletion NM_004700.3:c.806_808del NM_004700.3:c.806_808delCCT NM_172163.3:c.803CCT[1] NP_751895.1:p.Ser269del inframe deletion NC_000001.11:g.40819441CCT[1] NC_000001.10:g.41285113CCT[1] NG_008139.3:g.40655CCT[1] LRG_1378:g.40655CCT[1] LRG_1378t1:c.803CCT[1] LRG_1378p1:p.Ser269del - Protein change
- S269del
- Other names
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- Canonical SPDI
- NC_000001.11:40819438:CTCCTCCT:CTCCT
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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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KCNQ4 | - | - |
GRCh38 GRCh37 |
353 | 373 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2023 | RCV000484405.13 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 20, 2015 | RCV000656422.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 26, 2018 | RCV000825943.12 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 27, 2023 | RCV001089683.8 |
Submissions - Germline
Classification
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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
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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
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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 27, 2023)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001245167.2
First in ClinVar: May 04, 2020 Last updated: Oct 07, 2023 |
Comment:
The c.803_805CCT[1] (aka c.806_808del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino … (more)
The c.803_805CCT[1] (aka c.806_808del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Ser269del). It is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in at least 5 probands with autosomal dominant hearing loss (PS4_Supporting; PMID: 23399560, 23443030, 34316018, LMM unpublished data SCV000967428.1). The variant has been observed to segregate with hearing loss in 12 affected individuals from 1 family (PP1_Strong; PMID: 23443030). This variant causes a change in the length of the protein due to an in-frame deletion between the S5 membrane-spanning domain and the pore region, which is important for protein function (PM4, PMID: 23717403). Patch-clamp studies in HEK293T cells revealed significantly reduced whole-cell potassium currents, and KCNQ openers did not rescue KCNQ4 mutant channels (PMID: 34316018, PS3_Moderate). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM4, PS3_Moderate, PM2_Supporting, PS4_Supporting. (VCEP specifications version 2; 06.27.2023). (less)
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Uncertain significance
(Feb 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967428.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser269del variant in KCNQ4 has been reported in 2 individuals with bilateral sloping hear ing loss … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser269del variant in KCNQ4 has been reported in 2 individuals with bilateral sloping hear ing loss and segregated with disease in 9 affected relatives from 1 family (Wata be 2013, Abdelfatah 2013). However, there was one individual with a similar hear ing loss pattern and two additional individuals with other forms of hearing loss that did not harbor the variant, as well as 7 family members with hearing loss on the other side of the family that did not harbor the variant (Abdelfatah 2013 ). The p.Ser269del variant was absent from large population studies and is repor ted in ClinVar (Variation ID# 204595). This variant is a deletion of 1 amino aci d at position 269 and is not predicted to alter the protein reading-frame. In su mmary, while there is some suspicion for a pathogenic role, the clinical signifi cance of the p.Ser269del variant is uncertain. ACMG/AMP Criteria applied: PP1_St rong, PM2, PS4_Supporting, BS4. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jul 11, 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: SCV000568660.6
First in ClinVar: Apr 27, 2017 Last updated: Jul 22, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Lee et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant … (more)
Published functional studies demonstrate a damaging effect (Lee et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301388, 23399560, 33367117, 23443030, 34316018, 23717403, 30311386) (less)
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Pathogenic
(Oct 24, 2023)
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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: SCV004291790.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant, c.806_808del, results in the deletion of 1 amino acid(s) of the KCNQ4 protein (p.Ser269del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.806_808del, results in the deletion of 1 amino acid(s) of the KCNQ4 protein (p.Ser269del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant non-syndromic deafness (PMID: 23399560, 23443030). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208366). For these reasons, this variant has been classified as Pathogenic. (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: SCV000778434.1
First in ClinVar: Jun 12, 2018 Last updated: Jun 12, 2018 |
Ethnicity/Population group: Canadian/Japanese
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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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Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss. | Lee SY | Experimental & molecular medicine | 2021 | PMID: 34316018 |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL. | Abdelfatah N | European journal of human genetics : EJHG | 2013 | PMID: 23443030 |
Moderate hearing loss associated with a novel KCNQ4 non-truncating mutation located near the N-terminus of the pore helix. | Watabe T | Biochemical and biophysical research communications | 2013 | PMID: 23399560 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fb0e0e45-d5c2-4b0f-8f5f-3d89cb430f20 | - | - | - | - |
Text-mined citations for rs797044966 ...
HelpRecord last updated Apr 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.