rs956666801
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM5PM1
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
Consequence
NM_004700.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.825G>C | p.Trp275Cys | missense_variant | 5/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.825G>C | p.Trp275Cys | missense_variant | 5/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.825G>C | p.Trp275Cys | missense_variant | 5/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.513G>C | p.Trp171Cys | missense_variant | 4/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.144G>C | non_coding_transcript_exon_variant | 2/11 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461684Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 727170
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Nonsyndromic genetic hearing loss Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Oct 18, 2023 | 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 provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2024 | 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) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 31, 2016 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at