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  • Gene obtained from curated document aligns with ClinVar but not with the Allele Registry data


Variant: NM_004700.4(KCNQ4):c.803_805CCT[1] (p.Ser269del)

208366 (ClinVar)

Gene: KCNQ4
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
UUID: fb0e0e45-d5c2-4b0f-8f5f-3d89cb430f20
Approved on: 2023-06-27
Published on: 2023-10-05

HGVS expressions

NM_004700.4:c.803_805CCT[1]
NM_004700.4(KCNQ4):c.803_805CCT[1] (p.Ser269del)
NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)

Pathogenic

Met criteria codes 5
PS3_Moderate PM4 PM2_Supporting PS4_Supporting PP1_Strong
Not Met criteria codes 2
PP3 PM1

Evidence Links 1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
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in at least 5 probands with autosomal dominant hearing loss (PS4_Supporting; PMID: 23399560, 23443030, 34316018, LMM unpublished data SCV000967428.1).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).
Met criteria codes
PS3_Moderate
VCEP decided to upgrade from supporting to moderate level based on quality of evidence on call from 8.16.2023.

PM4
Although this deletion only shortens the peptide chain by one amino acid, it occurs between the S5 membrane-spanning domain and the pore region, which may be crucial for protein function.
PM2_Supporting
Absent from gnomAD with high coverage.
PS4_Supporting
LMM unpublished data: 2 probands -1 4yo female with moderate sloping SNHL. Also had astigmatism and a family history of HL. Mother was unaffected and negative for variant. Also het. for 2 VUS, 1 each in EPS8 and PCDH15. -9mo female with congenital unilateral mild sensorineural hearing loss with a family history of hearing loss. Het. for same PCDH15 variant and a VUS in ADCY1. Total: 5 probands (2 from LMM, 3 from published literature)
PP1_Strong
12 segregations from Abdelfatah family
Not Met criteria codes
PP3
REVEL score not provided for indels; conservation data not applicable. Splicing is not predicted to be impacted.
PM1
Not located between amino acids 270-297.
Curation History
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