The KCNQ1 NM_000218.3:c.1766G>A (NP_000209.2:p.(Gly589Asp)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: G589D produced no IKs current and markedly reduced cell-surface expression in KCNE1-context functional assays, with only one non-independent paper available. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen; ClinVar ID 3140).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.KCNQ1 provides instructions for a voltage-gated potassium channel that helps heart muscle cells reset between beats and maintain a normal rhythm. Changes in this gene are associated with inherited long QT syndrome type 1, Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation; it is also involved in genomic imprinting and the chromosome region linked to Beckwith-Wiedemann syndrome. KCNQ1 has no established general role in cancer.
The recorded framework is ClinGen KCNQ1 VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
Met: REVEL score 0.863 meets the VCEP PP3 threshold of ≥0.75 for this missense variant.
Not applicable: the KCNQ1 VCEP explicitly excludes PP5 at every strength level.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3, PP3, and PP5, each at supporting strength, total 3 points under the KCNQ1 Expert Panel framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.863. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen KCNQ1 VCEP v1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 13 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS3 supporting: G589D produced no IKs current and markedly reduced cell-surface expression.
PP3 supporting: REVEL 0.863 exceeds the VCEP cutoff of 0.75.
PP5 supporting: the ClinGen Potassium Channel Arrhythmia Expert Panel classified the variant as Pathogenic.
No criteria match.
PS3 is met at Supporting strength. PMID:15140888 directly studied KCNQ1 p.Gly589Asp (G589D) using approved functional assay types: cell-surface immunostaining and whole-cell electrophysiology with and without KCNE1 co-expression. G589D showed markedly reduced cell-surface expression and no IKs current; the paper's direct result is, "No IKs was observed with G589D and R591H." This supports a damaging effect on KCNQ1 function and trafficking. The VCEP strength-calibration material assigns a single consistent functional assay to PS3_Supporting and requires additional consistent independent assay evidence for higher strength; the two readouts here are from the same paper and are therefore not independent. Human review is retained because the extracted report does not provide the quantitative current magnitude, statistical comparison, or assay-control details needed to independently confirm the VCEP electrophysiology caveat beyond the reported absent current and KCNE1 context.
Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. ... Electrophysiology result can only meet PS3 if the variant is co-expressed with KCNE1 and the current magnitude is outside the normal range defined by the paper and is statistically significantly different from the normal control.
The VCEP applies PP3 to computational evidence supporting a deleterious effect and specifies REVEL and SpliceAI as preferred predictors. This is a missense variant, and the VCEP PP3 threshold is met by the REVEL score of 0.863, which is greater than or equal to 0.75. SpliceAI is not pathogenic-range for this rule (maximum delta score 0.004, below 0.2), but PP3 is met through the named REVEL path; no additional predictor is needed or counted.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc) ... * REVEL and SpliceAI are the preferred predictors ... * Apply this code if REVEL score is greater than or equal to 0.75.
Expert panel ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PM1 is not met. The KCNQ1 VCEP limits PM1 to a rare variant within the pore helix at amino acids 300 to 320, a region described as critical and without likely benign or benign variation in gnomAD. The variant is p.(Gly589Asp) at residue 589, outside residues 300-320, so the VCEP-defined PM1 route does not apply; no alternate hotspot route is provided by this VCEP rule.
Located in a mutational hot spot and/or critical and well-established functional domain (_e.g._ active site of an enzyme) without benign variation ... * The variant must be rare (meeting PM2\_Supporting) in order to be considered for PM1. ... * Met by a rare variant within the pore\u00a0helix (amino acids 300 to 320). This region is known to be a critical region of KCNQ1 and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD.
BS3 is not met. PMID:15140888 reports damaging rather than normal functional findings for p.Gly589Asp: markedly reduced cell-surface expression and no IKs current. These results do not show no damaging effect on protein function or splicing and therefore cannot support BS3. The VCEP's electrophysiology requirement for BS3 additionally requires KCNE1 co-expression, current within the paper's normal range, and no statistically significant difference from normal control; the reported absent IKs current is incompatible with that benign-readout requirement.
Well-established _in vitro_ or _in vivo_ functional studies show no damaging effect on protein function or splicing. ... Electrophysiology result can only meet BS3 if the variant is co-expressed with KCNE1 and if the variant current magnitude is within the normal range defined by the paper and is NOT statistically significantly different from the normal control.
The VCEP BP4 missense path requires both REVEL <0.25 and no predicted splicing defect by SpliceAI, with all four donor/acceptor delta scores <0.1. The variant is missense and its SpliceAI maximum delta score is 0.004, satisfying the splice component, but REVEL is 0.863 and therefore does not satisfy the required REVEL <0.25 condition. BP4 is consequently not met; the REVEL result is not reused as PP3 evidence here.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) ... * REVEL and SpliceAI are the preferred predictors ... * Apply this code for a missense variant if the REVEL score is <0.25 AND no splicing defect is predicted according to SpliceAI. ... * Use SpliceAI to look for a possible splicing defect. Apply this code if delta score for donor gain, donor loss, acceptor gain, or acceptor loss is <0.1 (in addition to REVEL score <0.25).
PS1 cannot be assessed from the available evidence. The variant is p.(Gly589Asp), and ClinVar documents the same c.1766G>A variant as Pathogenic by the KCNQ1 Expert Panel, but PS1 requires a previously established pathogenic comparison variant with the same amino-acid change and a different nucleotide change, classified without PS1. No qualifying alternate-nucleotide p.Gly589Asp comparison variant was identified; the same variant itself is not a comparison variant. SpliceAI for the case variant is 0.004, but the required comparison variant is absent.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. ... * The comparison variant must reach a pathogenic classification using these rule specifications, and must have reached pathogenic without the use of the PS1 code. ... * SpliceAI must be used to ensure that the comparison variant is not causing a splicing defect.
Not assessed. The available case evidence establishes the variant as a coding missense variant but provides no proband-level documentation of disease phenotype, parental genotypes, confirmed maternity and paternity, trio testing, or absence of a relevant family history. The VCEP-specific PS2 strength also requires phenotype-specific and proband-count information that is unavailable.
PS2
The KCNQ1 VCEP requires the variant not to meet BS1 and requires affected probands with QTc >=460 ms; supporting PS4 requires 2 independent observations, moderate requires 3-5 probands, and strong requires 6 or more probands. The literature packet lists multiple PS4 candidates, but it provides no verified affected-patient counts, QTc values, author-overlap resolution, or case-control table for this variant. PMID:12690509 was verified and reports screening 165 bodies found in water, with no KCNQ1-Fin:Gly589Asp carriers; this is not an affected-patient case series and supplies no case-control enrichment estimate. PMID:15140888 was verified as a functional trafficking/electrophysiology study, not a clinical case-control study. gnomAD v3.1 non-cancer reports 8/147930 alleles overall and 8/10622 Finnish alleles, but no matched affected-case count is available, so an OR and 95% CI cannot be computed. PS4 cannot be evaluated from the available evidence.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
The governing VCEP permits PM2 only at the Supporting level when the maximum allele frequency in one of five named continental populations—African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian—is below 0.00001 (0.001%). The default all-comers gnomAD v2.1 and v4.1 queries both failed, so this maximum cannot be evaluated. The available non-cancer subset results are not substituted because the VCEP PM2 rule does not specify a non-cancer or exome-only source.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... Supporting level only ... Maximum allele frequency in gnomAD (in one of the 5 continental populations; African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian) <0.00001 (0.001%)
The KCNQ1 VCEP pilot-results row for NM_000218.3:c.1766G>A (p.Gly589Asp) lists PM3_Supporting, but the available evidence does not identify an affected proband with this variant, a pathogenic second KCNQ1 variant, or parental/offspring testing establishing that the variants are in trans. The VCEP PM3 rule therefore cannot be independently evaluated from the available phase and allelic evidence.
For recessive disorders, detected in trans with a pathogenic variant; this requires testing of parents (or offspring) to determine phase, and both variants must be classified using these rule specifications.
PM5 cannot be assessed. The variant is a novel missense change at residue 589, but the available same-residue search found zero comparator candidates and returned no qualifying pathogenic or likely pathogenic alternate missense variant. Therefore, the required different missense change at the same residue, highly conserved across all five human KCNQ paralogues and classified under the VCEP rules without PM5, is not documented in the available evidence.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... * Caveat: Residue must be highly conserved across all 5 human KCNQ paralogues in order to be considered for PM5. To confirm conservation, curators should access paralogue data and regions of alignment and non-alignment between KCNQ1 and KCNQ2, KCNQ3, KCNQ4, and KCNQ5 at the site below: [https://www.cardiodb.org/paralogue_annotation/gene.php?name=KCNQ1](https://www.cardiodb.org/paralogue_annotation/gene.php?name=KCNQ1). ... * Poor conservation (ineligibility for PM5) is defined whenever 1 or more KCNQ’s show a different amino acid at the position. ... * Comparison variants must have a Pathogenic or Likely Pathogenic classification reached using these VCEP-specified rules without using PM5. ... * Variants at any codon where a likely benign / benign variant has been classified by the group are not eligible for PM5. ... * SpliceAI must be used to examine both variants for similar predicted effect or lack of effect on splicing (SpliceAI Δ score \<0.2). ... * Not used at the PM5\_Strong level.
Not assessed. Although the variant is coding, the available case evidence does not document an assumed de novo occurrence in a proband, parental testing status, absence of QT prolongation or sudden unexplained death in the family, qualifying phenotype specificity, or the number of probands needed to assign PM6 strength under the VCEP rule.
PM6
Not assessed. The available evidence contains no affected family members with documented variant carriage and no QTc, Schwartz score, or syncope data to determine whether family members qualify for counting. Therefore, the VCEP thresholds for PP1 Supporting, Moderate, or Strong cannot be evaluated.
PP1
The VCEP requires QT prolongation above 480 ms AND swimming-associated events, a treadmill stress-test result, or T-wave morphology characteristic of LQT1. The available case evidence does not provide a patient-specific QTc measurement or any of the three LQT1-specific phenotype features, so PP4 cannot be evaluated.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. * QT prolongation above 480ms AND * Swimming-associated events OR * Treadmill stress test result (PMID: 21699858) OR * T-wave morphology characteristic of LQT1 (PMID: 7586261, 29141844)
The governing VCEP rule requires the maximum allele frequency in one of five named continental populations—African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian—to be at least 0.004 (0.4%). The default all-comers gnomAD v2.1 and v4.1 queries both failed, so the required population-specific maximum cannot be evaluated. The available non-cancer subset results are not used because the VCEP rule does not specify a non-cancer or exome-only source for BA1.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... Maximum allele frequency in gnomAD (in one of the 5 continental populations; African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian) greater than or equal to 0.004 (0.4%).
The governing VCEP rule requires the maximum allele frequency in one of five named continental populations—African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian—to be at least 0.0004 (0.04%). The default all-comers gnomAD v2.1 and v4.1 queries both failed, so the required population-specific maximum cannot be evaluated. The available non-cancer subset results are not used because the VCEP rule does not specify a non-cancer or exome-only source for BS1.
Allele frequency is greater than expected for disorder ... Maximum allele frequency in gnomAD (in one of the 5 continental populations; African/African-American, East Asian, European non-Finnish, Latino/Admixed-American, or South Asian) greater than or equal to 0.0004 (0.04%).
Not assessed. The available evidence identifies no affected family member who lacks the variant and supplies no family-member QTc, Schwartz score, or syncope data. Consequently, neither the VCEP BS4 Supporting threshold of one qualifying non-carrier nor the Strong threshold of two or more can be evaluated.
BS4
The VCEP permits BP5 only when a variant is found in a case with an alternate molecular basis and the phenotype matches another LQTS form caused by KCNH2, SCN5A, or KCNE1, or when phenotype details are insufficiently specific; it is not applicable when the phenotype indicates KCNQ1. The available evidence contains no case-level alternate pathogenic variant, no alternate molecular diagnosis, and no phenotype details sufficient to determine which VCEP path applies. BP5 therefore cannot be assessed.
Variant found in a case with an alternate molecular basis for disease
PVS1 is not applicable because the variant is a missense substitution, NM_000218.3:c.1766G>A, producing p.(Gly589Asp), whereas the KCNQ1 VCEP PVS1 rule applies only to truncating variants affecting codons 1-676. No PVS1 strength is assigned.
For truncating variants, apply PVS1 at default (VeryStrong) level if the variant affects codons 1-581, since nonsense-mediated decay is predicted.
PM4 is not applicable because the variant is a missense substitution producing p.(Gly589Asp), not an in-frame insertion, in-frame deletion, or stop-loss variant that changes protein length under the KCNQ1 VCEP rule.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants
PP2 is not applicable to KCNQ1 under the governing VCEP specification. The rule explicitly excludes PP2 because benign variation is present throughout KCNQ1, with a missense constraint Z-score of 1.83, lower than 3.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease * Not applicable due to presence of benign variation throughout the _KCNQ1_ gene (since the missense constraint Z-score in gnomAD is 1.83, lower than 3).
The VCEP explicitly marks BS2 not applicable because KCNQ1-related disease has incomplete penetrance, and specifically notes that hearing loss and other phenotypes are not completely penetrant in homozygotes. Therefore, population observations cannot satisfy this criterion under the governing rule.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. ... Not applicable due to incomplete penetrance. ... Please note that hearing loss and other phenotypes are not completely penetrant in homozygotes (PMID: 23392653, https://www.ncbi.nlm.nih.gov/books/NBK1405/#jln.Summary).
BP1 is not applicable to KCNQ1 under the governing VCEP specification. The VCEP states that pathogenic KCNQ1 variants are not limited to truncating variants and can be missense, which directly excludes this missense variant from BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease * Not applicable, as pathogenic _KCNQ1_ variants are not limited to truncating variants, but can be missense as well.
The KCNQ1 VCEP expressly excludes BP2 because KCNQ1 has biallelic disease cases associated with Jervell and Lange-Nielsen syndrome. Therefore BP2 is not applicable regardless of whether a cis or trans observation is otherwise reported.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. ... Not applicable to KCNQ1 due to biallelic cases (Jervell and Lange-Nielsen syndrome)
BP3 is explicitly not applicable to KCNQ1 under the VCEP specification, regardless of repeat-region context; the variant is also a missense substitution rather than an in-frame deletion or insertion.
In-frame deletions/insertions in a repetitive region without a known function ... Not applicable to _KCNQ1_
The KCNQ1 VCEP marks BP6 as not applicable at every strength level and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No BP6 assertion is made.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule is scoped to synonymous variants and specified intronic variants, with additional exon-boundary and splice-site exclusions. NM_000218.3:c.1766G>A is a missense coding variant producing p.(Gly589Asp), so it lies outside BP7's governing scope. BP7 is therefore not_applicable regardless of its SpliceAI or conservation results.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Every interpreted variant in KCNQ1, mapped onto the exon structure of NM_000218.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
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The gnomAD v4.1 query FAILED for this variant, so its frequency in v4.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
Not available in gnomAD-Canada v1.0.
The VCEP applies PP3 to computational evidence supporting a deleterious effect and specifies REVEL and SpliceAI as preferred predictors. This is a missense variant, and the VCEP PP3 threshold is met by the REVEL score of 0.863, which is greater than or equal to 0.75. SpliceAI is not pathogenic-range for this rule (maximum delta score 0.004, below 0.2), but PP3 is met through the named REVEL path; no additional predictor is needed or counted.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc) ... * REVEL and SpliceAI are the preferred predictors ... * Apply this code if REVEL score is greater than or equal to 0.75.
The VCEP BP4 missense path requires both REVEL <0.25 and no predicted splicing defect by SpliceAI, with all four donor/acceptor delta scores <0.1. The variant is missense and its SpliceAI maximum delta score is 0.004, satisfying the splice component, but REVEL is 0.863 and therefore does not satisfy the required REVEL <0.25 condition. BP4 is consequently not met; the REVEL result is not reused as PP3 evidence here.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) ... * REVEL and SpliceAI are the preferred predictors ... * Apply this code for a missense variant if the REVEL score is <0.25 AND no splicing defect is predicted according to SpliceAI. ... * Use SpliceAI to look for a possible splicing defect. Apply this code if delta score for donor gain, donor loss, acceptor gain, or acceptor loss is <0.1 (in addition to REVEL score <0.25).
The VCEP BP7 rule is scoped to synonymous variants and specified intronic variants, with additional exon-boundary and splice-site exclusions. NM_000218.3:c.1766G>A is a missense coding variant producing p.(Gly589Asp), so it lies outside BP7's governing scope. BP7 is therefore not_applicable regardless of its SpliceAI or conservation results.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.470181.
8 paper records listed. 1 cited in the classification.
No IKs was observed with G589D and R591H
Location Results, "Mistrafficking of Reported LQT1 Mutants in This Region"; Fig. 8A-B; Discussion
Context KCNQ1 mutant expression in heterologous cells, assessed by cell-surface immunostaining and whole-cell electrophysiology, with and without KCNE1 co-expression.
Fig.1A–C Detection of specific founder mutations in the KCNQ1 and KCNH2 genes (KCNQ1-Fin:Gly589Asp and KCNH2-Fin:Leu552Ser) using the primer extention method.
Materials and methods, DNA analysis; Results and discussion; Figure 1 caption
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
The gnomAD v4.1 query FAILED for this variant, so its frequency in v4.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Pathogenic by ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3140)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.470181.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.