rs956666801

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPP3PM5PM1

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA21112664/MONDO:0019497/005

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

17
1
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.825G>C p.Trp275Cys missense_variant Exon 5 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.825G>C p.Trp275Cys missense_variant Exon 5 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.825G>C p.Trp275Cys missense_variant Exon 5 of 13 5 ENSP00000423756.2 P56696-2
KCNQ4ENST00000443478.3 linkc.510G>C p.Trp170Cys missense_variant Exon 4 of 13 5 ENSP00000406735.3 H0Y6N7
KCNQ4ENST00000506017.1 linkn.144G>C non_coding_transcript_exon_variant Exon 2 of 11 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461684
Hom.:
0
Cov.:
36
AF XY:
0.00000138
AC XY:
1
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Feb 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 275 of the KCNQ4 protein (p.Trp275Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. ClinVar contains an entry for this variant (Variation ID: 505302). 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 with a positive predictive value of 95%. This variant disrupts the p.Trp275 amino acid residue in KCNQ4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25116015, 31995783). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Jan 19, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30311386, 32746448, 25116015, 23717403) -

Nonsyndromic genetic hearing loss Pathogenic:1
Oct 18, 2023
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Likely pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

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). -

not specified Uncertain:1
Aug 31, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Trp275Cys variant in KCNQ4 has not been previously reported in individuals with hearing l oss and was absent from large population studies. The tryptophan (Trp) at positi on 275 is highly conserved in mammals and evolutionarily distant species, and co mputational prediction tools suggest the p.Trp275Cys may impact the protein. In addition, a different missense variant at the same amino acid position (p.Trp275 Arg) has been previously reported in an individual with hearing loss and segrega ted in 11 affected relatives (Wang 2014). These data suggest that a change at th is position may not be tolerated, however additional data is needed to assume pa thogenicity for this missense variant. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Trp275Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;H;H
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-12
.;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
.;D;D
Polyphen
1.0
D;D;D
Vest4
0.97, 0.95
MutPred
0.77
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.99
MPC
2.8
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs956666801; hg19: chr1-41285135; API