Variant: NM_000218.3(KCNQ1):c.840G>T (p.Val280=)

CA472038164

456870 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 7505299c-6dce-4844-8bbe-682038baf393

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.840G>T
NM_000218.3(KCNQ1):c.840G>T (p.Val280=)
NC_000011.10:g.2572905G>T
CM000673.2:g.2572905G>T
NC_000011.9:g.2594135G>T
CM000673.1:g.2594135G>T
NC_000011.8:g.2550711G>T
NG_008935.1:g.132915G>T
ENST00000496887.7:c.579G>T
ENST00000646564.2:c.478-10530G>T
ENST00000155840.12:c.840G>T
ENST00000335475.6:c.459G>T
ENST00000646564.1:c.124-10530G>T
ENST00000155840.9:c.840G>T
ENST00000335475.5:c.459G>T
ENST00000496887.6:c.579G>T
NM_000218.2:c.840G>T
NM_181798.1:c.459G>T

Likely Benign

• Met criteria codes: BP7 BP4

• Not Met criteria codes: PP1 PP3 PM1 PM2 PS3 PS4 BA1 BS2 BS1 BS4 BS3

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.840G>T (p.Val280=) is a synonymous variant in exon 6. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001610, with 19 alleles out of 1,180,028 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.06 for acceptor gain which is below the ClinGen Potassium Channel Arrhythmia VCEP BP7 threshold of <0.2 and does not strongly predict a splicing defect (BP4). In addition, the conservation tool PhyloP gives this variant a score of 0.275, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• BP7: The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.06 for acceptor gain which is below the ClinGen Potassium Channel Arrhythmia VCEP BP7 threshold of <0.2 and does not strongly predict a splicing defect. In addition, the conservation tool PhyloP gives this variant a score of 0.275, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7).
• BP4: The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.06 for acceptor gain which is below the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and does not strongly predict a splicing defect (BP4).

Not Met criteria codes

• PP1: Mastermind Genomenon search identified 0 articles
• PP3: No REVEL Score Splice AI no predicted splicing defect
• PM1: Not located in aa 300-320 per KCNQ1 VCEP
• PM2: gnomad v4.0 European (non-Finnish) is present in 19 out of 1,111,996 which is 0.0017% Not less than 0.001% as set by KCNQ1 VCEP
• PS3: Mastermind Genomenon search identified 0 articles
• PS4: Mastermind Genomenon search identified 0 articles
• BA1: gnomad v4.0 European (non-Finnish) is present in 19 out of 1,111,996 which is 0.0017% not greater than 0.1% cut off per KCNQ1 VCEP
• BS2: Mastermind Genomenon search identified 0 articles
• BS1: This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001610, with 19 alleles / out of 1,180,028 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met.
• BS4: Mastermind Genomenon search identified 0 articles
• BS3: Per KCNQ1 VCEP, do not use Meiler lab tool for synonymous variants using Meiler lab KCNQ1 functional impact predictor, there was no functional impact. This would be 1 independent electrophysiology/experimental/structural/functional simulation study which is supporting evidence for BS3