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

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: PM4 PM2_Supporting PS4_Supporting PP1_Strong PS3_Moderate

• Not Met criteria codes: PM1 PP3

Expert Panel

Hearing Loss VCEP

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

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in at least 5 probands with autosomal dominant hearing loss (PS4_Supporting; PMID: 23399560, 23443030, 34316018, LMM unpublished data SCV000967428.1).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

• 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• PS4_Supporting: LMM unpublished data: 2 probands -1 4yo female with moderate sloping SNHL.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
• PS3_Moderate: VCEP decided to upgrade from supporting to moderate level based on quality of evidence on call from 8.16.2023.

Not Met criteria codes

• PM1: Not located between amino acids 270-297.
• PP3: REVEL score not provided for indels; conservation data not applicable. Splicing is not predicted to be impacted.

Approved on: 2023-06-27

Published on: 2023-10-05