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NM_004700.4(KCNQ4):c.825G>C (p.Trp275Cys) AND Nonsyndromic genetic hearing loss

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 18, 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:
RCV000710319.3

Allele description [Variation Report for NM_004700.4(KCNQ4):c.825G>C (p.Trp275Cys)]

NM_004700.4(KCNQ4):c.825G>C (p.Trp275Cys)

Gene:
KCNQ4:potassium voltage-gated channel subfamily Q member 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.2
Genomic location:
Preferred name:
NM_004700.4(KCNQ4):c.825G>C (p.Trp275Cys)
Other names:
NM_004700.3(KCNQ4):c.825G>C(p.Trp275Cys); NM_004700.3(KCNQ4):c.825G>C
HGVS:
  • NC_000001.11:g.40819463G>C
  • NG_008139.3:g.40677G>C
  • NM_004700.4:c.825G>CMANE SELECT
  • NM_172163.3:c.825G>C
  • NP_004691.2:p.Trp275Cys
  • NP_751895.1:p.Trp275Cys
  • LRG_1378t1:c.825G>C
  • LRG_1378:g.40677G>C
  • LRG_1378p1:p.Trp275Cys
  • NC_000001.10:g.41285135G>C
  • NG_008139.1:g.40452G>C
  • NG_008139.2:g.40452G>C
  • NM_004700.3:c.825G>C
Protein change:
W275C
Links:
dbSNP: rs956666801
NCBI 1000 Genomes Browser:
rs956666801
Molecular consequence:
  • NM_004700.4:c.825G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172163.3:c.825G>C - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000840505ClinGen Hearing Loss Variant Curation Expert Panel
reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)		Likely Pathogenic
(Oct 18, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV000840505.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.825G>C variant in KCNQ4 is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 275 (p.Trp275Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928, which is above the threshold of 0.7, evidence that correlates with impact to KCNQ4 function (PP3). This variant has been reported in one individual with hearing loss and segregated in an affected first degree relative (SCV000712456.1). This variant is located within the pore-forming intramembrane region (amino acids 271-292) where many variants that cause autosomal dominant hearing loss are located and is defined as a critical functional domain by the ClinGen Hearing Loss VCEP (PM1; PMID: 23717403). A different missense variant at the same codon (p.Trp275Arg) has been classified as Pathogenic by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID 204597, PMID: 25116015). In summary, this variant is classified as Likely Pathogenic for autosomal dominant sensorineural hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PM1, PM5. (VCEP specifications version 2; 10.18.2023).

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

Last Updated: Jul 29, 2024