Variant: NM_000218.3(KCNQ1):c.1120C>T (p.Leu374Phe)

CA379133956

2124553 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 68a20f1a-2aa9-4c7c-b625-fe7989736201

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.1120C>T
NM_000218.3(KCNQ1):c.1120C>T (p.Leu374Phe)
NC_000011.10:g.2585299C>T
CM000673.2:g.2585299C>T
NC_000011.9:g.2606529C>T
CM000673.1:g.2606529C>T
NC_000011.8:g.2563105C>T
NG_008935.1:g.145309C>T
ENST00000496887.7:c.771+1754C>T
ENST00000646564.2:c.588+1754C>T
ENST00000155840.12:c.1120C>T
ENST00000335475.6:c.739C>T
ENST00000646564.1:c.234+1754C>T
ENST00000155840.9:c.1120C>T
ENST00000335475.5:c.739C>T
NM_000218.2:c.1120C>T
NM_181798.1:c.739C>T

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: PS4 PS1 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.1120C>T is a missense variant in KCNQ1 predicted to replace leucine with phenylalanine at position 374 (p.Leu374Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is rare and has been reported in at least 1 proband potentially affected with long QT syndrome 1, however, the phenotype has not been described in sufficient detail for the PP4 code and the requirement for 2 unrelated probands has not been reached, so the PS4_Supporting code is not yet met (PMID: 29688407). Another missense variant in the same codon, NM_000218.3(KCNQ1):c.1121T>A (p.Leu374His), (PMID: 15840476; PMID: 19716085) has been classified as a VUS for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 cannot be met, although no benign missense variants have been identified in this codon. A missense substitution in the equivalent codon of the paralogue KCNQ2, NM_172107.4(KCNQ2):c.1016T>G (p.Leu339Arg), has been reported in ClinVar in association with benign familial neonatal seizures (Accession: SCV000041606.3). However, this KCNQ2 variant encodes a different amino acid substitution and has not yet been classified by the ClinGen KCNQ Channel Brain Disorders VCEP, so PS1_Moderate is not met. The computational predictor REVEL gives a score of 0.873, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criterion to be classified as a variant of uncertain significance for long QT syndrome 1, as specified by the ClinGen Potassium Channel Arrhythmia VCEP; PM2_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.873, 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).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant is rare and has been reported in at least 1 proband potentially affected with long QT syndrome 1, however, the phenotype has not been described in sufficient detail and the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met (PMID: 29688407).
• PS1: A missense substitution in the equivalent codon of the paralogue KCNQ2, NM_172107.4(KCNQ2):c.1016T>G (p.Leu339Arg), has been reported in ClinVar in association with benign familial neonatal seizures (Accession: SCV000041606.3). However, this KCNQ2 variant encodes a different amino acid substitution and has not yet been classified by the ClinGen KCNQ Channel Brain Disorders VCEP, so PS1_Moderate is not met.
• PM5: Another missense variant in the same codon, NM_000218.3(KCNQ1):c.1121T>A (p.Leu374His), (PMID: 15840476; PMID: 19716085) has been classified as a VUS for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 cannot be met, although no benign missense variants have been identified in this codon. This residue has been confirmed to be highly conserved across all 5 human KCNQ paralogues, and SpliceAI has been used to confirm that neither variant has a predicted impact on KCNQ1 splicing.