Variant: NM_000218.3(KCNQ1):c.1766G>A (p.Gly589Asp)

CA006347

3140 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: fd00310f-d874-429b-827d-7cef2c3e1d1f

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.1766G>A
NM_000218.3(KCNQ1):c.1766G>A (p.Gly589Asp)
NC_000011.10:g.2778009G>A
CM000673.2:g.2778009G>A
NC_000011.9:g.2799239G>A
CM000673.1:g.2799239G>A
NC_000011.8:g.2755815G>A
NG_008935.1:g.338019G>A
ENST00000496887.7:c.1409G>A
ENST00000646564.2:c.1226G>A
ENST00000155840.12:c.1766G>A
ENST00000335475.6:c.1385G>A
ENST00000526095.2:c.170G>A
ENST00000646564.1:c.872G>A
ENST00000155840.9:c.1766G>A
ENST00000335475.5:c.1385G>A
ENST00000526095.1:n.273G>A
NM_000218.2:c.1766G>A
NM_181798.1:c.1385G>A

Pathogenic

• Met criteria codes: PM2_Supporting PS3 PS4 PP3 PM3_Supporting

• Not Met criteria codes: BS1 PP4 PP1 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.1766G>A is a missense variant in KCNQ1 that substitutes glycine with aspartic acid at codon 589. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0000008.474, with 1 allele / 1,180,024 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). Please note that the variant has a higher frequency of 0.0005504 (35 alleles / 63,586 total alleles) in the European Finnish population. which is not one of the 5 continental populations eligible to meet a population code. The variant has been reported in 34 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 11216980). The variant has also been detected in at least 2 apparently unrelated probands with Jervell and Lange-Nielsen syndrome who had both a long QTc interval and congenital deafness. 1 proband was compound heterozygous for this variant and the p.Tyr171Ter variant, which has not yet been classified by the VCEP, confirmed in trans by family testing, while the other proband was homozygous for the variant (0.5 pts, PM3_Supporting, PMID: 11216980). The variant has been reported to segregate with long QT syndrome 1 through the proband and at least 1 confirmed affected family member with QTc >480 ms, however, this does not meet the requirement of at least 2 segregations to meet PP1 (PMID: 11216980). This variant has been reported in at least one affected proband exhibiting QTc prolongation and an exercise-related syncopal spell, however the QTc is not available to evaluate in relation to the required threshold of >480 ms, so PP4 is not met (PMID: 10483966). The computational predictor REVEL gives a score of 0.863, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in experimental assays from at least 5 independent research groups, including manual patch-clamp (PMID: 11216980, PMID: 25344363, PMID: 22095730, PMID: 11799244), electrophysiology studies in iPSC-derived cardiomyocytes (PMID: 15528464), and cell surface localization (PMID: 25344363). The combination of 5 electrophysiology studies with 1 protein metabolism study satisfies the VCEP requirement for the strong level of the experimental code (PS3). Another missense variant in the same codon, c.1765G>A (p.Gly589Ser) has been reported in association with long QT syndrome 1 (PMID: 31565860), however, PM5 has not been considered in order to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4, PM2_Supporting, PM3_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0000008.474, with 1 allele / 1,180,024 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). Please note that the variant has a higher frequency of 0.0005504 (35 alleles / 63,586 total alleles) in the European Finnish population. which is not one of the 5 continental populations eligible to meet a population code.
• PS3: This variant has been shown to disrupt KCNQ1 function in experimental assays from at least 5 independent research groups, including manual patch-clamp (PMID: 11216980, PMID: 25344363, PMID: 22095730, PMID: 11799244), electrophysiology studies in iPSC-derived cardiomyocytes (PMID: 15528464), and cell surface localization (PMID: 25344363). The combination of 5 electrophysiology studies with 1 protein metabolism study satisfies the VCEP requirement for the strong level of this code (PS3).
• PS4: This variant is rare and has been reported in 34 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 11216980).
• PP3: The computational predictor REVEL gives a score of 0.863, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The computational splicing predictor SpliceAI gives a score of 0.00 for all splicing disruption types, 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.
• PM3_Supporting: This variant has been detected in at least 2 apparently unrelated probands with Jervell and Lange-Nielsen syndrome who had both a long QT interval and congenital deafness. 1 proband was compound heterozygous for this variant and the p.Tyr171Ter variant, which has not yet been classified by the VCEP, confirmed in trans by family testing (PMID: 11216980). The other proband was homozygous for the variant (0.5 pts, PM3_Supporting, PMID: 11216980).

Not Met criteria codes

• BS1: This variant is present in gnomAD v.2.1.1 at a maximum allele frequency of 0.0005625, with 14 alleles / 24888 total alleles in the European Finnish population. Although this is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001, European Finnish is not one of the 5 eligible continental populations, so no population code is met.
• PP4: This variant has been reported in at least one affected proband exhibiting QTc prolongation and an exercise-related syncopal spell, however the QTc is not available to evaluate in relation to the required threshold of >480 ms, so PP4 is not met (PMID: 10483966).
• PP1: The variant has been reported to segregate with long QT syndrome 1 through the proband and at least 1 confirmed affected family member with QTc >480 ms, however, this does not meet the requirement of at least 2 segregations to meet PP1 (PMID: 11216980).
• PM5: Another missense variant in the same codon, c.1765G>A (p.Gly589Ser) has been reported in association with long QT syndrome 1 (PMID: 31565860), however, PM5 has not been considered in order to avoid circularity.