Variant: NM_000218.3(KCNQ1):c.817C>G (p.Leu273Val)

CA379131380

1950175 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 4b2b9d1f-1be3-4c19-900c-39be9c72566b

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.817C>G
NM_000218.3(KCNQ1):c.817C>G (p.Leu273Val)
NC_000011.10:g.2572882C>G
CM000673.2:g.2572882C>G
NC_000011.9:g.2594112C>G
CM000673.1:g.2594112C>G
NC_000011.8:g.2550688C>G
NG_008935.1:g.132892C>G
ENST00000496887.7:c.556C>G
ENST00000646564.2:c.478-10553C>G
ENST00000155840.12:c.817C>G
ENST00000335475.6:c.436C>G
ENST00000646564.1:c.124-10553C>G
ENST00000155840.9:c.817C>G
ENST00000335475.5:c.436C>G
ENST00000496887.6:c.556C>G
NM_000218.2:c.817C>G
NM_181798.1:c.436C>G

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PS3_Moderate PM5_Supporting

• Not Met criteria codes: BP3 BP2 BP4 BP1 BP7 BP5 PS4 PS2 PS1 BA1 PP4 PP2 PP1 PM1 PM4 PM3 PM6 BS2 PVS1 BS4 BS1

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.817C>G (p.Leu273Val) is a missense variant in KCNQ1 that replaces leucine with valine at codon 273. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000001695, with 2 alleles / 1180024 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). Another missense variant NM_000218.3(KCNQ1):c.817C>T (p.Leu273Phe) in the same codon has been classified as likely pathogenic for long QT syndrome by the ClinGen Potassium Channel Arrhythmia VCEP, while no benign missense variants have been identified in this codon (PM5_Supporting). 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. The computational predictor REVEL gives a score of 0.822, (which is above the threshold of 0.75, evidence that correlates with impact to KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in at least three experimental assays, including Manual patch-clamp and Experimental/Structural/Functional Simulation (PS3_Moderate; PMID: 15649981, PMID: 29021305, PMID: 36674868). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3_Moderate, PM2_Supporting, PM5_Supporting, and 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 0.822, (which is above the threshold of 0.75, evidence that correlates with impact to KCNQ1 function (PP3).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000001695, with 2 alleles / 1180024 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting).
• PS3_Moderate: This variant has been shown to disrupt KCNQ1 function in at least three experimental assays, including Manual patch-clamp and Experimental/Structural/Functional Simulation (PS3_Moderate; PMID: 15649981, PMID: 29021305, PMID: 36674868).
• PM5_Supporting: Another missense variant NM_000218.3(KCNQ1):c.817C>T (p.Leu273Phe) in the same codon has been classified as likely pathogenic for long QT syndrome by the ClinGen Potassium Channel Arrhythmia VCEP, while no benign missense variants have been identified in this codon (PM5_Supporting). 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.

Not Met criteria codes

• BP3: Missense variant
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: The computational predictor REVEL gives a score of 0.822, (which is above the threshold of 0.75, evidence that correlates with impact to KCNQ1 function (PP3).
• BP1: Not applicable, as pathogenic KCNQ1 variants are not limited to truncating variants, but can be missense as well.
• BP7: Missense variant
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant is rare and has been reported in 1 proband affected with long QT syndrome 1, however, the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met (PMID: 36674868).
• PS2: 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: Insufficient evidence to be considered highly specific: Proband had QTc interval 480-500, no history of syncope. Family history of SCD while swimming in untested relative. Simulation of ECG available to review only.
• PP2: Not applicable due to presence of benign variation throughout the KCNQ1 gene (since the missense constraint Z-score in gnomAD is 1.83, lower than 3).
• PP1: Each affected family member must have Schwartz score (PMID: 22083145) >3.5 or QTc >480ms or syncope in order to be included / counted. The proband + 2 affected family members with the variant meets PP1. Father carrier 425. Paternal aunt and 2 paternal cousins carriers QTc 422, 433, 430. Paternal great-uncle (genetic testing not performed) died at age 30 due to SCD while swimming. Maternal family history of DCM in 2 uncles. PMID: 36674868
• PM1: Amino acid 300-320 is considered hot spot
• PM4: Missense variant
• 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
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: Missense
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline