Variant: NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)

CA008122

3118 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: e51d0786-c264-49fa-8d86-240837d2afbd

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.760G>A
NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)
NC_000011.10:g.2572089G>A
CM000673.2:g.2572089G>A
NC_000011.9:g.2593319G>A
CM000673.1:g.2593319G>A
NC_000011.8:g.2549895G>A
NG_008935.1:g.132099G>A
ENST00000496887.7:c.499G>A
ENST00000646564.2:c.478-11346G>A
ENST00000155840.12:c.760G>A
ENST00000335475.6:c.379G>A
ENST00000646564.1:c.124-11346G>A
ENST00000155840.9:c.760G>A
ENST00000335475.5:c.379G>A
ENST00000496887.6:c.499G>A
NM_000218.2:c.760G>A
NM_181798.1:c.379G>A

Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PP1_Strong PP3 PP4 PS3_Supporting

• Not Met criteria codes: PM5

Expert Panel

Potassium Channel Arrhythmia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Potassium Channel Arrhythmia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ1 Version 1.0.0

Evidence submitted by expert panel

Potassium Channel Arrhythmia VCEP

NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)‌ is a missense variant in KCNQ1 predicted to replace valine with methionine at amino acid 254. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in affected probands exhibiting QTc prolongation above 480 milliseconds and an exercise-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID: 29439887). This variant has been reported in at least 4 additional probands affected with long QT syndrome 1 (PS4_Moderate; PMID: 29439887). The variant segregates with long QT syndrome through 10 affected family members of the 5 probands confirmed to be similarly affected by exhibiting QTc prolongation above 480 milliseconds and/or syncope and/or Schwartz score above 3.5 (PP1_Strong, PMID: 29439887). An additional family has been reported but has not been described in sufficient detail to be considered for family segregation (PMID: 8528244). The computational predictor REVEL gives a score of 0.918, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant has been shown to disrupt KCNQ1 function in two required experimental assays, both of them manual patch-clamp studies reporting a dominant negative electrophysiological defect (PS3_Supporting; PMID: 10376919, PMID: 14756674). In summary, this variant meets the criterion to be classified as pathogenic for long QT syndrome 1, as specified by the ClinGen Potassium Channel Arrhythmia VCEP; PS3_Supporting, PS4_Moderate PM2_Supporting, PP1_Strong, PP3, PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• PS4_Moderate: This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1 (PS4_Moderate; PMID: 29439887). A family with an additional proband has been reported but has not been described in sufficient detail to be considered for inclusion in proband counting (PMID: 8528244).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PP1_Strong: This variant has been reported to segregate with long QT syndrome 1 through 5 probands and 10 total family members confirmed to be similarly affected by exhibiting QTc prolongation above 480 milliseconds and/or syncope and/or Schwartz score above 3.5 (PP1_Strong, PMID: 29439887). An additional family has been reported but has not been described in sufficient detail to be considered for family segregation (PMID: 8528244).
• PP3: The computational predictor REVEL gives a score of 0.918, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP threshold of >0.5 and does not strongly predict that the variant disrupts the splicing of KCNQ1 (PP3).
• PP4: This variant has been reported in at least four affected probands exhibiting QTc prolongation above 480 milliseconds and an-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID: 29439887).
• PS3_Supporting: This variant has been shown to disrupt KCNQ1 function in two required experimental assays, both of them manual patch-clamp studies reporting a dominant negative electrophysiological defect, (PS3_Supporting; PMID: 10376919, PMID: 14756674).

Not Met criteria codes

• PM5: Another missense variant in the same codon, NM_000218.3(KCNQ1):c.760G>T (p.Val254Leu) has been reported in association with long QT syndrome 1 (PMID: 14678125, PMID: 16414944), while no benign missense variants have been identified in this codon. While neither variant is predicted by SpliceAI to impact KCNQ1 splicing, this residue is not highly conserved across all 5 human KCNQ paralogues, so PM5_Supporting has not been considered.