Variant: NM_000218.3(KCNQ1):c.604+3_604+6dup

CA934459766

871729 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: a9bd7890-c427-4c7a-a351-1402e4e16842

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.604+3_604+6dup
NM_000218.3(KCNQ1):c.604+3_604+6dup
NC_000011.10:g.2570757_2570760dup
CM000673.2:g.2570757_2570760dup
NC_000011.9:g.2591987_2591990dup
CM000673.1:g.2591987_2591990dup
NC_000011.8:g.2548563_2548566dup
NG_008935.1:g.130767_130770dup
ENST00000496887.7:c.343+3_343+6dup
ENST00000646564.2:c.478-12678_478-12675dup
ENST00000155840.12:c.604+3_604+6dup
ENST00000335475.6:c.223+3_223+6dup
ENST00000646564.1:c.124-12678_124-12675dup
ENST00000155840.9:c.604+3_604+6dup
ENST00000335475.5:c.223+3_223+6dup
ENST00000496887.6:c.343+3_343+6dup
NM_000218.2:c.604+3_604+6dup
NM_181798.1:c.223+3_223+6dup

Uncertain Significance

• Met criteria codes: BP4 PM2_Supporting

• Not Met criteria codes: BP7

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.604+3_604+6dup is a variant in intron 3 that duplicates four base pairs adjacent to exon 3. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000002542, with 3 alleles / 1,179,978 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). The computational splicing predictor SpliceAI gives a score of 0.07 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing (BP4). This intronic variant is located within one of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and so is not eligible for the BP7 code. 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: PM2_Supporting and BP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• BP4: The computational splicing predictor SpliceAI gives a score of 0.07 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing (BP4).
• PM2_Supporting: This variant is present in gnomAD v.4.0.0 at a maximum allele frequency of 0.000002542, with 3 alleles / 1179978 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).

Not Met criteria codes

• BP7: This intronic variant is located within one of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and so is not eligible for the BP7 code.