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NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del) AND Nonsyndromic genetic hearing loss

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 27, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001089683.8

Allele description [Variation Report for NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)]

NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)

Gene:
KCNQ4:potassium voltage-gated channel subfamily Q member 4 [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
1p34.2
Genomic location:
Preferred name:
NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)
HGVS:
  • NC_000001.10:g.41285111_41285113del
  • NC_000001.11:g.40819441CCT[1]
  • NG_008139.3:g.40655CCT[1]
  • NM_004700.3:c.806_808del
  • NM_004700.4:c.803CCT[1]MANE SELECT
  • NM_172163.3:c.803CCT[1]
  • NP_004691.2:p.Ser269del
  • NP_751895.1:p.Ser269del
  • LRG_1378t1:c.803CCT[1]
  • LRG_1378:g.40655CCT[1]
  • LRG_1378p1:p.Ser269del
  • NC_000001.10:g.41285111_41285113del
  • NC_000001.10:g.41285113CCT[1]
  • NC_000001.10:g.41285116_41285118delCCT
  • NC_000001.11:g.40819441_40819443CCT[1]
  • NM_004700.2:c.806_808delCCT
  • NM_004700.3:c.806_808delCCT
  • NM_004700.4(KCNQ4):c.803_805CCT[1]MANE SELECT
Protein change:
S269del
Links:
dbSNP: rs797044966
NCBI 1000 Genomes Browser:
rs797044966
Molecular consequence:
  • NM_004700.4:c.803CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_172163.3:c.803CCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:
Nonsyndromic genetic hearing loss
Synonyms:
Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:
MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001245167ClinGen Hearing Loss Variant Curation Expert Panel
reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)		Pathogenic
(Jun 27, 2023) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss.

Lee SY, Choi HB, Park M, Choi IS, An J, Kim A, Kim E, Kim N, Han JH, Kim MY, Lee SM, Oh DY, Kim BJ, Yi N, Kim NKD, Lee C, Park WY, Koh YI, Gee HY, Cho HS, Kang TM, Choi BY.

Exp Mol Med. 2021 Jul;53(7):1192-1204. doi: 10.1038/s12276-021-00653-4. Epub 2021 Jul 28.

PubMed [citation]
PMID:
34316018
PMCID:
PMC8333092

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV001245167.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 24, 2024