Variant classification summary

NM_000218.3:c.1766G>A

KCNQ1 · NP_000209.2:p.(Gly589Asp) · NM_000218.3

GRCh37: chr11:2799239 G>A · GRCh38: chr11:2778009 G>A

Gene: KCNQ1 Transcript: NM_000218.3

Final call

VUS

PS3 supporting PP3 supporting PP5 supporting

Variant details

Gene

KCNQ1

Transcript

NM_000218.3

Protein

NP_000209.2:p.(Gly589Asp)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: G589D produced no IKs current and markedly reduced cell-surface expression.

2

PP3 supporting: REVEL 0.863 exceeds the VCEP cutoff of 0.75.

3

PP5 supporting: the ClinGen Potassium Channel Arrhythmia Expert Panel classified the variant as Pathogenic.

Final determination: Under the KCNQ1 VCEP's Tavtigian-style point framework, 3 supporting points fall within the 0–5-point Uncertain Significance range.

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.1766G>A is a missense variant producing p.(Gly589Asp), not a truncating variant covered by the KCNQ1 PVS1 rule.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no qualifying alternate-nucleotide pathogenic p.Gly589Asp comparison variant was available, although the case variant itself is expert-panel Pathogenic.	clinvar spliceai pm5_candidates
PS2	Not assessed	Not assessed: parental genotypes, confirmed maternity and paternity, family history, and qualifying proband phenotype data are unavailable.	cspec
PS3	Met	Met at Supporting: G589D produced no IKs current and markedly reduced cell-surface expression in KCNE1-context functional assays, with only one non-independent paper available.	cspec vcep_05_31_24_kcnq1_ps3_bs3_strength_overview vcep_05_31_24_ps3_bs3_functional_assays_kcnq1 PMID:15140888
PS4	Not assessed	Not assessed: no verified affected-case count with QTc >=460 ms or matched control comparison is available to evaluate the VCEP's PS4 thresholds.	cspec gnomad_v4 PMID:12690509 PMID:15140888
PM1	Not met	Not met: p.(Gly589Asp) is at residue 589, outside the VCEP-approved pore-helix PM1 region of residues 300-320.	cspec
PM2	Not assessed	Not assessed: default all-comers gnomAD queries failed, so the VCEP's required maximum frequency below 0.00001 (0.001%) cannot be evaluated.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: the VCEP row lists PM3_Supporting, but no affected-proband, pathogenic-in-trans-partner, or parental phase evidence is available.	cspec vcep_kcnq1_pilot_results_final
PM4	N/A	Not applicable: p.(Gly589Asp) is a missense substitution and does not cause the in-frame insertion, deletion, or stop-loss protein-length change required for PM4.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the available search found zero qualifying alternate missense comparator variants at residue 589 for the required PM5 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: assumed de novo status, parental-testing status, family history, qualifying phenotype, and proband count are undocumented.	cspec
PP1	Not assessed	Not assessed: no affected relatives with variant carriage or qualifying QTc, Schwartz score, or syncope data are documented.	cspec
PP2	N/A	Not applicable: the KCNQ1 VCEP excludes PP2 because benign variation is present throughout the gene and its missense constraint Z-score is 1.83.	cspec
PP3	Met	Met: REVEL score 0.863 meets the VCEP PP3 threshold of ≥0.75 for this missense variant.	cspec revel spliceai
PP4	Not assessed	Not assessed: no patient-specific QTc above 480 ms plus swimming events, treadmill result, or characteristic LQT1 T-wave morphology is documented.	cspec
PP5	Met	Not applicable: the KCNQ1 VCEP explicitly excludes PP5 at every strength level.	cspec clinvar
BA1	Not assessed	Not assessed: default all-comers gnomAD queries failed, so the VCEP's required maximum frequency threshold of 0.004 (0.4%) cannot be evaluated.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: default all-comers gnomAD queries failed, so the VCEP's required maximum frequency threshold of 0.0004 (0.04%) cannot be evaluated.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the VCEP excludes BS2 because KCNQ1 disease has incomplete penetrance, including incompletely penetrant phenotypes in homozygotes.	cspec
BS3	Not met	Not met: G589D showed no IKs current and reduced surface expression, rather than a normal functional readout required for BS3.	cspec vcep_05_31_24_kcnq1_ps3_bs3_strength_overview vcep_05_31_24_ps3_bs3_functional_assays_kcnq1 PMID:15140888
BS4	Not assessed	Not assessed: no qualifying affected non-carrier relatives or QTc, Schwartz score, or syncope data are documented.	cspec
BP1	N/A	Not applicable: the KCNQ1 VCEP excludes BP1 because pathogenic KCNQ1 variants include missense variants, not only truncating variants.	cspec
BP2	N/A	Not applicable: the KCNQ1 VCEP excludes BP2 because biallelic Jervell and Lange-Nielsen syndrome cases occur.	cspec
BP3	N/A	Not applicable: the KCNQ1 VCEP explicitly excludes BP3, and this variant is missense rather than an in-frame insertion or deletion.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.863 exceeds the VCEP BP4 missense cutoff of <0.25 despite SpliceAI maximum delta 0.004.	cspec revel spliceai
BP5	Not assessed	Not assessed: no case-level alternate molecular basis or phenotype details establish either the VCEP's alternate-LQTS path or its KCNQ1 exclusion.	cspec
BP6	N/A	Not applicable: the KCNQ1 VCEP explicitly excludes BP6 at every strength level.	cspec
BP7	N/A	Not applicable: c.1766G>A is a missense variant, whereas the VCEP BP7 rule covers synonymous and specified intronic variants.	cspec

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