ClinVar Genomic variation as it relates to human health
NM_004700.4(KCNQ4):c.853G>A (p.Gly285Ser)
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.853G>A (p.Gly285Ser)
Variation ID: 6241 Accession: VCV000006241.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40819893 (GRCh38) [ NCBI UCSC ] 1: 41285565 (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 Sep 11, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004700.4:c.853G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004691.2:p.Gly285Ser missense NM_172163.3:c.853G>A NP_751895.1:p.Gly285Ser missense NC_000001.11:g.40819893G>A NC_000001.10:g.41285565G>A NG_008139.3:g.41107G>A LRG_1378:g.41107G>A LRG_1378t1:c.853G>A LRG_1378p1:p.Gly285Ser P56696:p.Gly285Ser - Protein change
- G285S
- Other names
- NM_004700.3(KCNQ4):c.853G>A(p.Gly285Ser)
- NM_004700.3(KCNQ4):c.853G>A
- Canonical SPDI
- NC_000001.11:40819892:G:A
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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) |
no assertion criteria provided
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Jan 14, 2011 | RCV000006619.17 | |
Pathogenic (1) |
reviewed by expert panel
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Sep 11, 2018 | RCV000211722.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2018 | RCV000844633.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 13, 2022 | RCV002512841.9 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Sep 11, 2018)
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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: SCV000840524.4
First in ClinVar: Jun 01, 2016 Last updated: Dec 11, 2022 |
Comment:
The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with … (more)
The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID: 10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P. (less)
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Pathogenic
(Oct 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198442.4
First in ClinVar: Jan 30, 2015 Last updated: Aug 31, 2019 |
Comment:
The p.Gly285Ser variant in KCNQ4 has been reported in at least three individuals with hearing loss, and segregated with disease in over 15 affected relatives … (more)
The p.Gly285Ser variant in KCNQ4 has been reported in at least three individuals with hearing loss, and segregated with disease in over 15 affected relatives fr om two families (LMM unpublished data, Kubisch 1999, Wang 2014). It was absent f rom large population studies. In vitro functional studies support an impact on p rotein function and suggest that the variant may act in a dominant-negative mann er (Kubisch 1999, Bal 2008). Furthermore, the p.Gly285Ser variant falls within t he highly conserved pore-forming region of KCNQ4 (Oza 2018). Supporting the into lerance of this position to variation, a different amino acid change at the same position (p.Gly285Cys) has been reported in one family with hearing loss (Couck e 1999). Finally, this variant was classified as Pathogenic on 9/11/2018 by the ClinGen-approved Hearing Loss Expert Panel (Variation ID 6241). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant no nsyndromic hearing loss. ACMG/AMP criteria applied: PP1_Strong, PM1, PM2, PP3, P S3_Supporting, PS4_Supporting. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 13, 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: SCV003523272.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly285 amino acid residue in KCNQ4. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly285 amino acid residue in KCNQ4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8035838, 10369879, 20832469, 20966080, 23717403). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 10025409, 20966080, 23750663). 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. ClinVar contains an entry for this variant (Variation ID: 6241). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10025409, 25116015). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the KCNQ4 protein (p.Gly285Ser). (less)
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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: SCV000026802.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 24, 2019 |
Comment on evidence:
In a family with autosomal dominant deafness (DFNA2A; 600101), Kubisch et al. (1999) identified a gly285-to-ser (GGC-to-AGC) mutation in heterozygous state. This mutation segregated with … (more)
In a family with autosomal dominant deafness (DFNA2A; 600101), Kubisch et al. (1999) identified a gly285-to-ser (GGC-to-AGC) mutation in heterozygous state. This mutation segregated with all affected members in the pedigree and was not found on 150 control Caucasian chromosomes. Kim et al. (2011) referred to this mutation as resulting from an 853G-A transition in exon 6, resulting in a G285S substitution in the pore region of the protein. (less)
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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: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000041116.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Ethnicity/Population group: Northern European, Han Chinese
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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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Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. | Oza AM | Human mutation | 2018 | PMID: 30311386 |
DFNA2 Nonsyndromic Hearing Loss. | Adam MP | - | 2018 | PMID: 20301388 |
Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss. | Wang H | PloS one | 2014 | PMID: 25116015 |
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 |
Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation. | Naito T | PloS one | 2013 | PMID: 23717403 |
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 |
Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. | Bal M | The Journal of biological chemistry | 2008 | PMID: 18786918 |
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. | Coucke PJ | Human molecular genetics | 1999 | PMID: 10369879 |
KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. | Kubisch C | Cell | 1999 | PMID: 10025409 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a39fbdff-7b49-469e-8890-5baad55ff075 | - | - | - | - |
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Text-mined citations for rs28937588 ...
HelpRecord last updated Apr 15, 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.