LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-02
Case ID: NM_000218.3_c.1032G_A_20261102_091539
Framework: ACMG/AMP 2015
Variant classification summary

NM_000218.3:c.1032G>A

KCNQ1  · NP_000209.2:p.(Ala344=)  · NM_000218.3
GRCh37: chr11:2604775 G>A  ·  GRCh38: chr11:2583545 G>A
Gene: KCNQ1 Transcript: NM_000218.3
Final call
Likely Pathogenic
PS3 strong PS4 supporting PM2 supporting PP3 supporting PP4 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
KCNQ1
Transcript
NM_000218.3
Protein
NP_000209.2:p.(Ala344=)
gnomAD AF
1.242884486315842e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 Strong was supported by aberrant splicing and impaired KCNQ1 channel function.
2
Likely Pathogenic: PS4 Supporting was met by multiple independent affected probands with QTc measurements at least 460 ms.
3
Likely Pathogenic: PM2 Supporting was met because the maximum qualifying gnomAD allele frequency was 1.701e-6.
4
Likely Pathogenic: PP3 Supporting was met because SpliceAI's maximum delta score was 0.49.
5
Likely Pathogenic: PP4 Supporting was met by swimming-triggered disease and exercise QTc prolongation to 500 ms.
6
Likely Pathogenic: PP5 Supporting was specified by the adjudicated criteria based on an expert-panel pathogenic assertion.
Final determination: Under the KCNQ1 VCEP point-based framework, PS3 Strong contributes 4 points and five Supporting criteria contribute 1 point each; the total of 9 points maps to Likely Pathogenic.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: c.1032G>A is synonymous, p.(Ala344=), while the VCEP PVS1 rule applies only to truncating variants.
cspec pvs1_variant_assessment PMID:10477533 PMID:17292394 PMID:21810471 PMID:29857160
PS1 N/A Not applicable: c.1032G>A is synonymous, p.Ala344=, so it makes no amino-acid change eligible for the VCEP's PS1 comparison rule.
cspec PMID:10477533
PS2 Not assessed Not assessed: de novo status was reported, but confirmed maternity/paternity, qualifying family history, and VCEP phenotype-strength data are undocumented.
cspec PMID:10477533
PS3 Met Met, Strong: patient-derived and heterologous assays showed aberrant exon skipping, full-length transcript reduction to 42.16% versus 91.94%, and markedly reduced or absent KCNQ1 current.
cspec vcep_05_31_24_ps3_bs3_functional_assays_kcnq1 vcep_kcnq1_pilot_results_final PMID:10477533 PMID:17292394 PMID:21810471 PMID:29857160
PS4 Met Met at Supporting: multiple independent c.1032G>A probands had QTc measurements >=460 ms, exceeding the VCEP requirement of two qualifying observations.
cspec gnomad_v4 PMID:10477533 PMID:21810471 PMID:22629021
PM1 N/A Not applicable: residue 344 lies outside the VCEP-defined PM1 pore-helix interval of amino acids 300-320, and no additional KCNQ1 domain-table regions are supplied.
cspec gnomad_v4 PMID:10477533
PM2 Met Met at Supporting: gnomAD v4.1 European non-Finnish maximum AF is 1.701e-6, below the VCEP PM2 cutoff of 1e-5.
cspec gnomad_v4 gnomad_v2
PM3 Not assessed Not assessed: c.1032G>A was reported in trans with c.569G>A, but the partner variant lacks a classification established under the KCNQ1 VCEP rules.
cspec PMID:22629021
PM4 N/A Not applicable: p.(Ala344=) causes no protein length change and is neither an in-frame indel nor a stop-loss variant.
cspec pvs1_variant_assessment PMID:10477533
PM5 N/A Not applicable: p.Ala344= is synonymous, whereas the VCEP PM5 rule requires a novel missense change.
cspec
PM6 Not assessed Not assessed: de novo status is reported, but parental/family-history requirements and VCEP phenotype-strength data are incomplete.
cspec PMID:10477533
PP1 Not assessed Not assessed: familial transmission is reported, but qualifying QTc, Schwartz-score, or syncope data needed to count affected relatives are unavailable.
cspec PMID:10477533 PMID:22629021
PP2 N/A Not applicable: the VCEP excludes PP2 for KCNQ1 because benign variation is present throughout the gene and its missense constraint Z-score is 1.83.
cspec
PP3 Met Met: SpliceAI maximum delta score 0.49, including donor-gain 0.49 and donor-loss 0.382, exceeds the VCEP PP3 threshold of ≥0.2.
cspec spliceai
PP4 Met Met at Supporting: the exact variant was associated with swimming-triggered cardiac arrest and exercise QTc prolongation to 500 ms, exceeding the VCEP threshold above 480 ms.
cspec PMID:29857160
PP5 Met Not applicable: the KCNQ1 VCEP explicitly prohibits use of PP5 regardless of available external classification assertions.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 European non-Finnish maximum AF is 1.701e-6, below the VCEP BA1 threshold of 0.004.
cspec gnomad_v4 gnomad_v2
BS1 Not met Not met: gnomAD v4.1 European non-Finnish maximum AF is 1.701e-6, below the VCEP BS1 threshold of 0.0004.
cspec gnomad_v4 gnomad_v2
BS2 N/A Not applicable: the KCNQ1 VCEP excludes BS2 because disease phenotypes are incompletely penetrant, including in homozygotes.
cspec gnomad_v4 gnomad_v2
BS3 Not met Not met: functional studies showed damaging effects, including full-length transcript reduction to 42.16% versus 91.94% and potassium current of only 41.4+/-9.5% of control.
cspec vcep_05_31_24_ps3_bs3_functional_assays_kcnq1 PMID:10477533 PMID:17292394 PMID:21810471 PMID:29857160
BS4 Not assessed Not assessed: no affected family member is documented to lack c.1032G>A, so neither the one-person nor two-person BS4 threshold is evaluable.
cspec PMID:10477533 PMID:22629021
BP1 N/A Not applicable: the VCEP excludes BP1 for KCNQ1 because pathogenic variants are not limited to truncating variants and include missense variants.
cspec
BP2 N/A Not applicable: the KCNQ1 VCEP excludes BP2 because biallelic KCNQ1 cases cause Jervell and Lange-Nielsen syndrome.
cspec
BP3 N/A Not applicable: the KCNQ1 VCEP explicitly excludes BP3 for KCNQ1, regardless of repeat-region context.
cspec
BP4 Not met Not met: SpliceAI maximum delta score 0.49 is above the VCEP BP4 synonymous-variant cutoff of <0.1.
cspec spliceai
BP5 N/A Not applicable: the reported phenotype is KCNQ1-consistent, whereas the VCEP limits BP5 to another LQTS phenotype or insufficiently specific clinical details.
cspec PMID:21810471 PMID:22629021 PMID:29857160
BP6 N/A Not applicable: the KCNQ1 VCEP explicitly prohibits use of BP6 regardless of available external benign assertions.
cspec
BP7 N/A Not applicable: The synonymous variant is at the last base of an exon, within the VCEP BP7 exclusion for the last three exon nucleotides.
cspec PMID:10477533
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