VCV000006243.13 - ClinVar

NM_004700.4(KCNQ4):c.961G>A (p.Gly321Ser)

Germline

Classification

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.

(7)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004700.4(KCNQ4):c.961G>A (p.Gly321Ser)

Variation ID: 6243 Accession: VCV000006243.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40820180 (GRCh38) [ NCBI UCSC ] 1: 41285852 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 2, 2016	Apr 20, 2024	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004700.4:c.961G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004691.2:p.Gly321Ser	missense
NM_004700.3:c.961G>A
NM_172163.3:c.961G>A	NP_751895.1:p.Gly321Ser	missense
NC_000001.11:g.40820180G>A
NC_000001.10:g.41285852G>A
NG_008139.3:g.41394G>A
LRG_1378:g.41394G>A
LRG_1378t1:c.961G>A	LRG_1378p1:p.Gly321Ser
	P56696:p.Gly321Ser

... more HGVS ... less HGVS

Protein change

G321S

Other names

Canonical SPDI

NC_000001.11:40820179:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA340534 UniProtKB: P56696#VAR_008728 OMIM: 603537.0003 dbSNP: rs28939710 VarSome

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
Gene	OMIM	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.
KCNQ4		-	-	GRCh38 GRCh37	380	400

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.
Autosomal dominant nonsyndromic hearing loss 2A	Likely pathogenic (4)	criteria provided, single submitter	Apr 11, 2023	RCV000006621.8
Rare genetic deafness	Likely pathogenic (1)	criteria provided, single submitter	Oct 14, 2020	RCV001195307.5
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2022	RCV002512842.4

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.
Likely pathogenic (Jan 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003522655.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 20966080‚ 23750663‚ 26515070‚ 10369879 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 20966080, 23750663, 26515070). 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: 6243). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 10369879; Invitae). This variant is present in population databases (rs28939710, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KCNQ4 protein (p.Gly321Ser). (less)
Likely Pathogenic (Oct 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rare genetic deafness (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001365632.2 First in ClinVar: Jul 04, 2020 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 9126484‚ 10369879‚ 23750663‚ 21951272 Comment: The p.Gly321Ser variant in KCNQ4 has been previously reported to segregate with autosomal dominant hearing loss in multiple individuals from a large Dutch family (Coucke … (more) The p.Gly321Ser variant in KCNQ4 has been previously reported to segregate with autosomal dominant hearing loss in multiple individuals from a large Dutch family (Coucke 1999 PMID: 10369879, Van Camp 1997 PMID: 9126484). It has also been identified in 0.006% (1/15414) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID 6243). Functional studies indicate that the variant results in a dominant negative effect (Leitner 2012 PMID: 21951272, Gao 2013 PMID: 23750663), and computational tools and conservation analyses also suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PP1_Moderate, PM2, PP3, PS3_Supporting. (less)
Pathogenic (Dec 01, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003931052.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: Published functional studies demonstrate p.(G321S) results in non-functional channels and significantly reduces KCNQ4 trafficking (Kim et al., 2011; Gao et al., 2013); Not observed at … (more) Published functional studies demonstrate p.(G321S) results in non-functional channels and significantly reduces KCNQ4 trafficking (Kim et al., 2011; Gao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34316018, 28340560, 23399560, 25525159, 31541171, 21951272, 26036578, 9126484, 8035838, 27619418, 18797286, 23776385, 25116015, 23717403, 11556850, 30556268, 27704564, 17033161, 36140355, 12408061, 24616153, 11252765, 28802383, Zhang2021[Review], 26515070, 10369879, 34824372, 34732400, 20966080, 23750663) (less)
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004173286.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Aug 20, 2015)	no assertion criteria provided Method: literature only	Autosomal dominant nonsyndromic hearing loss 2A Affected status: yes Allele origin: germline	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000777820.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018 Comment: This variant used to be reported in GeneReviews NBK1209.	Publications: PubMed (2) PubMed: 20301388‚ 26036578 BookShelf: NBK1209 BookShelf: NBK1209
Pathogenic (Nov 22, 2019)	no assertion criteria provided Method: literature only	DEAFNESS, AUTOSOMAL DOMINANT 2A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026804.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 24, 2019	Publications: PubMed (1) PubMed: 8035838 Comment on evidence: In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified a 961G-A transition in exon 7 of the KCNQ4 gene, … (more) In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified a 961G-A transition in exon 7 of the KCNQ4 gene, which was predicted to produce a gly321-to-ser (G321S) change in the S6 transmembrane domain of the protein. (less)
Likely pathogenic (Feb 26, 2019)	no assertion criteria provided Method: case-control	Autosomal dominant nonsyndromic hearing loss 2A Affected status: yes Allele origin: inherited	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital Accession: SCV000902326.1 First in ClinVar: May 12, 2019 Last updated: May 12, 2019	Number of individuals with the variant: 1 Clinical Features: hearing loss (present) Family history: yes

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 20966080, 23750663, 26515070). 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: 6243). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 10369879; Invitae). This variant is present in population databases (rs28939710, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KCNQ4 protein (p.Gly321Ser).

Comment:

The p.Gly321Ser variant in KCNQ4 has been previously reported to segregate with autosomal dominant hearing loss in multiple individuals from a large Dutch family (Coucke 1999 PMID: 10369879, Van Camp 1997 PMID: 9126484). It has also been identified in 0.006% (1/15414) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID 6243). Functional studies indicate that the variant results in a dominant negative effect (Leitner 2012 PMID: 21951272, Gao 2013 PMID: 23750663), and computational tools and conservation analyses also suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PP1_Moderate, PM2, PP3, PS3_Supporting.

Comment:

Published functional studies demonstrate p.(G321S) results in non-functional channels and significantly reduces KCNQ4 trafficking (Kim et al., 2011; Gao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34316018, 28340560, 23399560, 25525159, 31541171, 21951272, 26036578, 9126484, 8035838, 27619418, 18797286, 23776385, 25116015, 23717403, 11556850, 30556268, 27704564, 17033161, 36140355, 12408061, 24616153, 11252765, 28802383, Zhang2021[Review], 26515070, 10369879, 34824372, 34732400, 20966080, 23750663)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels.	Sihn CR	The Journal of biological chemistry	2016	PMID: 26515070
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
Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers.	Leitner MG	British journal of pharmacology	2012	PMID: 21951272
Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2.	Kim HJ	The Journal of biological chemistry	2011	PMID: 20966080
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.	Coucke PJ	Human molecular genetics	1999	PMID: 10369879
Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p.	Van Camp G	Genomics	1997	PMID: 9126484
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

Text-mined citations for rs28939710 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004700.4(KCNQ4):c.961G>A (p.Gly321Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28939710 ...