Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys)

CA21112664

505302 (ClinVar)

Gene: KCNQ4
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3e8e4973-8620-4a94-8c71-3bdec36a8281
Approved on: 2023-10-18
Published on: 2024-07-02

HGVS expressions

NM_004700.3:c.825G>C
NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys)
NC_000001.11:g.40819463G>C
CM000663.2:g.40819463G>C
NC_000001.10:g.41285135G>C
CM000663.1:g.41285135G>C
NC_000001.9:g.41057722G>C
NG_008139.1:g.40452G>C
NG_008139.2:g.40452G>C
NG_008139.3:g.40677G>C
ENST00000347132.10:c.825G>C
ENST00000347132.9:c.825G>C
ENST00000443478.3:c.511G>C
ENST00000506017.1:n.144G>C
ENST00000509682.6:c.825G>C
NM_172163.2:c.825G>C
NM_004700.4:c.825G>C
NM_172163.3:c.825G>C

Likely Pathogenic

Met criteria codes 4
PP3 PM1 PM5 PM2_Supporting
Not Met criteria codes 22
BP3 BP2 BP1 BP4 PVS1 BP7 BP5 PS1 PS2 PS3 PS4 PP2 PP4 PP1 PM4 PM3 PM6 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
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).
Met criteria codes
PP3
REVEL score of 0.928
PM1
The variant occurs in the KCNQ4 hot spot: between amino acids 271-292.
PM5
NM_004700.3(KCNQ4):c.823T>C (p.Trp275Arg) is classified as Path by the ClinVar staff PMID: 25116015 (segregated with HL in 11 family members), 20301388 NM_004700.3(KCNQ4):c.824G>C (p.Trp275Ser) is classified as LP by GeneDx. Also, c.827G>C (p.Trp276Ser) variant has been reported in ClinVar as Pathogenic by the LMM, OMIM, and GeneReviews.
PM2_Supporting
Absent from gnomAD
Not Met criteria codes
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL score of 0.928
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
LMM internal evidence - 1 AD segregation: a mother (progressive severe - profound) and daughter (mild-moderate at age 11)
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Absent from gnomAD
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Absent from gnomAD
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