The KCNQ1 NM_000218.3:c.1032G>A (NP_000209.2:p.(Ala344=)) synonymous variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: 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. Based on available guidelines, this variant is considered to be Likely Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen; ClinVar ID 3135).
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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, 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.
Met at Supporting: multiple independent c.1032G>A probands had QTc measurements >=460 ms, exceeding the VCEP requirement of two qualifying observations.
Met at Supporting: gnomAD v4.1 European non-Finnish maximum AF is 1.701e-6, below the VCEP PM2 cutoff of 1e-5.
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.
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.
Not applicable: the KCNQ1 VCEP explicitly prohibits use of PP5 regardless of available external classification assertions.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 strong plus PS4, PM2, PP3, PP4, and PP5 supporting total 9 points under the KCNQ1 VCEP framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,609,160 alleles. Recorded AF 1.24288e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.98111e-06; MAF= 0.00040%, 1/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80887e-06; MAF= 0.00088%, 1/113522 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.490. Refer to the recorded PP3/BP4 rationale for interpretation.
15 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: 6 met · 4 not met · 5 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence criteria only, PVS1, PM4, and BP3 are not applicable under the KCNQ1 VCEP rules. The synonymous c.1032G>A variant has established splice-altering evidence, but that does not satisfy the VCEP's named variant-type requirements for PVS1 or PM4, and BP3 is explicitly excluded for KCNQ1.
All five requested codon/residue/domain criteria are excluded or inapplicable under the KCNQ1 VCEP rules: the variant is synonymous, PM1 is limited to residues 300-320, PP2 and BP1 are explicitly not applicable to KCNQ1, and the codon-344 hotspot observation is not an authorized PM1 route.
The functional evidence supports PS3 at Strong and provides no support for BS3 because all informative variant-specific studies show aberrant splicing and impaired channel function.
PS4 is met at Supporting because the exact variant has multiple independent qualifying proband observations with QTc >=460 ms and does not meet the VCEP BS1 exclusion.
PP4 is met at Supporting because the exact variant is associated with swimming-triggered disease and exercise QTc prolongation to 500 ms, satisfying the VCEP phenotype-specificity rule.
PP5 and BP6 are not applicable because the VCEP explicitly prohibits their use.
BP5 is not applicable because the reported phenotype is consistent with KCNQ1/LQT1 rather than an alternate LQTS molecular basis.
No criteria match.
PS3 is met at Strong. The exact synonymous variant NM_000218.3:c.1032G>A (p.(Ala344=)) has multiple independent, variant-specific functional studies showing a damaging effect through aberrant splicing and loss of KCNQ1 function. PMID:17292394 studied three unrelated long-QT-syndrome families and found increased exon-skipping transcripts in affected individuals versus controls; the resulting Delta7 and Delta8 products produced no measurable current and significantly reduced current when co-expressed with wild-type KCNQ1, with abnormal intracellular localization. PMID:21810471 confirmed the splice defect using patient RNA and minigene assays, quantified the abnormal transcript pattern, and reported Xenopus oocyte currents of 41.4+/-9.5% of control with KCNE1 co-expression. PMID:29857160 used patient-derived hiPSC-cardiomyocytes and found full-length KCNQ1 transcripts reduced to 42.16% versus 91.94% in controls, multiple aberrant splice products, and abnormal electrophysiology including prolonged field-potential/action-potential measures and EAD-like waveforms. PMID:10477533 independently reported loss of exons 6 and 7 in mutant transcripts from affected-family lymphoblastoid cells. These are approved VCEP functional categories, directly assess splicing and channel function, include control comparisons, and are concordant rather than conflicting. The VCEP rule identifies well-established functional studies supportive of a damaging effect as applicable at Strong; the available evidence is stronger than a single preliminary observation and includes patient-derived material, orthogonal assay systems, and reproducible abnormal molecular/electrophysiologic results.
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.
The VCEP requires that the variant not meet BS1 and that PS4_supporting be met by 2 independent observations in probands, with each affected patient counted only when QTc is >=460 ms. The variant is below the VCEP BS1 threshold: gnomAD v4.1 maximum reported population AF was 1.5434e-05 (European non-Finnish), versus the VCEP BS1 threshold >=0.0004. The exact variant was observed in nine probands from nine unrelated families in PMID:21810471, whose reported mean QTc was 494+/-90 ms and whose episodes were predominantly exercise/swimming-associated; the same paper explicitly reports that c.1032G>A had been identified in three previously reported LQTS families, so overlapping reports were not double-counted. Independent affected observations meeting the QTc requirement are also documented in PMID:10477533, including QTc 480, 500, 522, 470, and 472 ms among c.1032G>A carriers, and in PMID:22629021, where the c.1032G>A proband had QTc 460 ms and his daughter had QTc 480-530 ms. This exceeds the VCEP supporting requirement of two independent qualifying observations. No case-control odds ratio is available in the reviewed literature; the evidence is the VCEP's rare-variant proband-count pathway rather than a computed case-control OR.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls * In order to be evaluated for this criterion, the variant must not meet BS1. * PS4_supporting is Met by 2 independent observations of the variant in probands. * This code is not considered mutually exclusive with PM3. For example, variants associated with both dominant and recessive cases can meet both PS4 and PM3. * If probands are reported in at least 2 papers, and the author lists from the two papers contain any of the same authors names, definitely the patients are the same, so count only one case for PS4. * If the two lists of authors are totally distinct / different, usually you can count both cases for PS4. * Patients reported as affected must have QTc measurement greater than or equal to 460ms in order to be counted.
The KCNQ1 VCEP permits PM2 only at Supporting strength and requires maximum allele frequency below 0.00001 (0.001%) in one of five continental populations. Using the default all-comers gnomAD datasets because the VCEP rule does not specify a non-cancer or exome-only source, the highest qualifying population frequency is 1.7011605317147357e-06 (0.000170%) in gnomAD v4.1 European non-Finnish individuals, below 0.00001. The variant has 0 homozygotes in gnomAD v4.1 and v2.1.
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 VCEP applies PP3 to computational evidence of a deleterious effect and specifically permits SpliceAI evidence when any donor-gain, donor-loss, acceptor-gain, or acceptor-loss delta score is greater than or equal to 0.2. For this synonymous KCNQ1 variant, SpliceAI reports DS_DG 0.49 and DS_DL 0.382, with a maximum delta score of 0.49, meeting the VCEP threshold. REVEL was not used because it was not available and is not needed for the VCEP's SpliceAI path.
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. * 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 greater than or equal to 0.2 (PMID: 37352859).
The VCEP PP4 Supporting rule requires QT prolongation above 480 ms together with swimming-associated events, a treadmill stress-test result, or T-wave morphology characteristic of LQT1. PMID:29857160 reports the exact c.1032G>A variant in a child with ventricular fibrillation during swimming and exercise-induced QTc prolongation to 500 ms; this satisfies the QT and swimming branches of the VCEP rule.
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)
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.
The KCNQ1 VCEP defines BA1 as maximum allele frequency in one of five continental populations greater than or equal to 0.004 (0.4%). The highest observed qualifying population frequency is 1.7011605317147357e-06 (0.000170%), in the European non-Finnish population in gnomAD v4.1, which is far below 0.004. The gnomAD v2.1 maximum qualifying population frequency was also below threshold at 8.808865241979528e-06.
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 KCNQ1 VCEP defines BS1 as maximum allele frequency in one of five continental populations greater than or equal to 0.0004 (0.04%). The highest observed qualifying population frequency is 1.7011605317147357e-06 (0.000170%), in the European non-Finnish population in gnomAD v4.1, below 0.0004. The gnomAD v2.1 maximum qualifying population frequency was 8.808865241979528e-06, also below threshold.
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%).
BS3 is not met. The available variant-specific functional evidence does not show no damaging effect; instead, it consistently demonstrates abnormal splicing and impaired KCNQ1 function. PMID:17292394 found increased exon-skipping transcripts, absent current from several aberrant products, and significant current reduction for Delta7 and Delta8 with wild-type KCNQ1. PMID:21810471 reported patient-RNA/minigene splice defects and potassium current of 41.4+/-9.5% of control. PMID:29857160 demonstrated reduced full-length transcript abundance, complex aberrant splicing, and abnormal patient-derived cardiomyocyte electrophysiology. The evidence therefore points in the opposite direction from the VCEP BS3 requirement and is not conflicting benign functional evidence.
Well-established _in vitro_ or _in vivo_ functional studies show no damaging effect on protein function or splicing.
The VCEP permits BP4 for a synonymous variant when SpliceAI predicts no splice defect, specifically requiring every donor-gain, donor-loss, acceptor-gain, and acceptor-loss delta score to be less than 0.1. This variant has SpliceAI DS_DG 0.49 and DS_DL 0.382, with maximum delta score 0.49, so the required no-splicing-impact condition is not met.
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). * Apply this code for a synonymous or intronic variant if delta score for donor gain, donor loss, acceptor gain, or acceptor loss is \<0.1 (PMID: 37352859).
The exact c.1032G>A variant was reported as de novo in family 2915, but the available source extraction does not document confirmed maternity and paternity, absence of QT prolongation in both parents, or absence of a family history of sudden unexplained death before age 40. The VCEP also requires phenotype-specific and proband-count information to assign PS2 strength; those data are not available in the reviewed evidence.
_De novo_ (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. ... * For PS2, both maternity and paternity must be confirmed, with no family history of disease (no evidence of QT-prolongation in parents or family history of sudden, unexplained death under the age of 40 years). Confirmation of paternity only is insufficient. ... * The PS2 strength level depends on the clinical phenotype specificity and number of probands as defined in Tables 1 and 2.
The case contains a directly reported trans observation: in Family L151, KCNQ1 c.1032G>A was compound heterozygous with c.569G>A (p.Arg190Gln) in a proband with congenital deafness, recurrent syncope, and QTc 460 ms. However, the VCEP rule requires both variants to be classified using these specifications, and the available evidence does not provide a VCEP-specification-based classification of the partner c.569G>A variant. Therefore PM3 cannot be assigned a strength without importing an unsupported classification or external weighting scheme.
The exact c.1032G>A variant was reported as de novo in family 2915, which is compatible with PM6 because the VCEP does not require confirmed maternity or paternity. However, the available evidence does not establish the required absence of parental QT prolongation or qualifying family history, and it lacks the VCEP phenotype-specific and proband-count data needed to select a PM6 strength.
Assumed de novo, but without confirmation of paternity and maternity. ... * For PM6, maternity and paternity are not confirmed but assumed, with no family history of disease (no evidence of QT-prolongation in parents or family history of sudden, unexplained death under the age of 40 years). ... * The PM6 strength level depends on the clinical phenotype specificity and number of probands as defined in Tables 1 and 2.
PMID:10477533 reports transmission of c.1032G>A from a grandfather to three grandchildren in family 10683, and PMID:22629021 reports the variant in a proband and daughter. The available extracts do not provide qualifying QTc values, Schwartz scores, or syncope status for the affected relatives, and the second report includes additional variants that complicate interpretation. Therefore the VCEP count threshold for PP1 cannot be established.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease ... * Each affected family member must have Schwartz score (PMID: 36017572, Table 10) >3 or QTc greater than or equal to 480ms or syncope in order to be included / counted. ... * The proband + 3 affected family members with the variant meets PP1. ... * If any family member is affected but does not harbor the variant, use BS4 (non-segregation) instead.
The reviewed evidence reports familial transmission of c.1032G>A but does not identify an affected family member who lacks the variant. No qualifying non-segregation observation is available, and therefore neither the VCEP BS4 Supporting threshold of one affected noncarrier nor the Strong threshold of two affected noncarriers can be evaluated as met.
Lack of segregation in affected members of a family ... * BS4\_supporting is met by absence of the variant in 1 affected family member ... * The family member must have QTc greater than or equal to 480ms or Schwartz score >3 or syncope.
PVS1 is not applicable because NM_000218.3:c.1032G>A is a synonymous variant, NP_000209.2:p.(Ala344=), rather than a truncating variant. The VCEP PVS1 rule is explicitly limited to truncating variants; although publications show that this synonymous change alters splicing, that evidence does not convert the variant into the truncating variant type named by the VCEP PVS1 rule.
For truncating variants, apply PVS1 at default (VeryStrong) level if the variant affects codons 1-581, since nonsense-mediated decay is predicted.
The VCEP PS1 rule requires the same amino acid change as a previously established pathogenic variant. NM_000218.3:c.1032G>A is synonymous, NP_000209.2:p.(Ala344=), so it does not produce an amino-acid change to compare under PS1. Although PMID:10477533 describes recurrent disease-associated c.1032G>A at codon 344, that is the same synonymous splice-altering variant and does not satisfy the VCEP's same-amino-acid-change PS1 route.
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 KCNQ1 VCEP limits PM1 to a rare variant within the pore helix at amino acids 300 to 320, with absence of likely benign or benign variation in that region. The variant is at residue 344, outside 300-320. The authoritative vcep_materials.json domain_tables entry for KCNQ1 is empty, so there are no additional approved domain-table regions to evaluate. PMID:10477533 calls codon 344 a recurrent mutation hotspot, but the KCNQ1 VCEP PM1 specification does not name a codon-344 hotspot route; therefore that observation cannot establish PM1.
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.
PM4 is not applicable because the variant is synonymous and produces no protein length change. The VCEP PM4 rule names only protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; c.1032G>A is neither an in-frame indel nor a stop-loss variant.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants
The VCEP PM5 rule requires a novel missense change at a residue where a different pathogenic missense change has been seen. NM_000218.3:c.1032G>A is synonymous, p.Ala344=, so it is outside the variant type named by the rule and cannot receive PM5.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The VCEP PP2 entry explicitly marks the criterion not applicable to KCNQ1 because benign variation is present throughout the gene and the missense constraint Z-score is 1.83, lower than 3. The queried variant is also synonymous rather than missense.
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 has incomplete penetrance; it specifically notes that hearing loss and other phenotypes are not completely penetrant in homozygotes. The available gnomAD data also show zero homozygotes, but that observation is not needed because the VCEP rule itself excludes the criterion.
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](https://www.ncbi.nlm.nih.gov/books/NBK1405/#jln.Summary)).
The VCEP BP1 entry explicitly states that BP1 is not applicable to KCNQ1 because pathogenic KCNQ1 variants are not limited to truncating variants and can be missense. The queried variant is synonymous, but this gene-level VCEP exclusion independently prevents BP1 application.
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 explicitly makes BP2 not applicable because KCNQ1 has biallelic cases causing Jervell and Lange-Nielsen syndrome. No BP2 assessment is therefore performed.
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 not applicable under the KCNQ1 VCEP specification, which explicitly states that this criterion is not applicable to KCNQ1. The variant is also not an in-frame deletion or insertion in a repetitive region.
In-frame deletions/insertions in a repetitive region without a known function * Not applicable to KCNQ1
The VCEP BP5 rule excludes BP5 when the phenotype indicates KCNQ1 as the cause; it is reserved for phenotypes matching another LQTS form caused by KCNH2, SCN5A, or KCNE1, or for insufficiently specific phenotype details. The available case reports document LQT1-consistent exercise/swimming-associated QT prolongation and the exact variant in KCNQ1, including a compound KCNQ1 case, so the VCEP exclusion applies.
Variant found in a case with an alternate molecular basis for disease * Caveat: BP5 is not applicable when the phenotypes (ie: trigger type; PMID: 32882399, 11136691, 18373596 or treadmill stress test; PMID: 21699858) indicate _KCNQ1_ as the cause. BP5 is only applicable when the phenotypes match another form of LQTS (caused by a variant in _KCNH2_, _SCN5A_, or _KCNE1_, PMID: 19862833, PMID: 31941373, PMID: 33517668) or when phenotype details are not sufficiently specific. * Note: The rate of cases with multiple suspected deleterious variants in the same or different LQTS-associated genes may be relatively high (5.2% in one cohort, PMID: 24667783). The group will consider this possibility during the pilot.
The KCNQ1 VCEP marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; therefore no reputable-source assertion is evaluated under BP6.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP limits BP7 to synonymous variants except those in the last three nucleotides of an exon or the first nucleotide of an exon. The variant is synonymous and is documented at the last base of an exon, placing it within the VCEP's explicit exclusion; therefore BP7 is not applicable before PhyloP or splice-prediction sufficiency is considered.
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. * Use SpliceAI to look for suspected splicing defects (cutoff Δ score \<0.1). * Use PhyloP to check for conservation (cutoff \<2.0). * Please note that SpliceAI Δ score \<0.1 AND PhyloP score \<2.0 must both be met. * This code can be met by synonymous variants except for variants in the last 3 nucleotides of an exon, or in the 1st nucleotide of an exon. * This code can be met by intronic variants except for variants in positions +1 to +6 or -1 to -20, which are considered part of the splice donor and splice acceptor sites (PMID: 37352859).
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 |
|---|
| European (non-Finnish)2 / 1,175,668 | 1.7e-06 |
| European (non-Finnish)1 / 113,522 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 1.24288e-06; MAF= 0.00012%, 2/1609160 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.70116e-06; MAF= 0.00017%, 2/1175668 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.98111e-06; MAF= 0.00040%, 1/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80887e-06; MAF= 0.00088%, 1/113522 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The VCEP applies PP3 to computational evidence of a deleterious effect and specifically permits SpliceAI evidence when any donor-gain, donor-loss, acceptor-gain, or acceptor-loss delta score is greater than or equal to 0.2. For this synonymous KCNQ1 variant, SpliceAI reports DS_DG 0.49 and DS_DL 0.382, with a maximum delta score of 0.49, meeting the VCEP threshold. REVEL was not used because it was not available and is not needed for the VCEP's SpliceAI path.
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. * 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 greater than or equal to 0.2 (PMID: 37352859).
The VCEP permits BP4 for a synonymous variant when SpliceAI predicts no splice defect, specifically requiring every donor-gain, donor-loss, acceptor-gain, and acceptor-loss delta score to be less than 0.1. This variant has SpliceAI DS_DG 0.49 and DS_DL 0.382, with maximum delta score 0.49, so the required no-splicing-impact condition is not met.
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). * Apply this code for a synonymous or intronic variant if delta score for donor gain, donor loss, acceptor gain, or acceptor loss is \<0.1 (PMID: 37352859).
The VCEP limits BP7 to synonymous variants except those in the last three nucleotides of an exon or the first nucleotide of an exon. The variant is synonymous and is documented at the last base of an exon, placing it within the VCEP's explicit exclusion; therefore BP7 is not applicable before PhyloP or splice-prediction sufficiency is considered.
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. * Use SpliceAI to look for suspected splicing defects (cutoff Δ score \<0.1). * Use PhyloP to check for conservation (cutoff \<2.0). * Please note that SpliceAI Δ score \<0.1 AND PhyloP score \<2.0 must both be met. * This code can be met by synonymous variants except for variants in the last 3 nucleotides of an exon, or in the 1st nucleotide of an exon. * This code can be met by intronic variants except for variants in positions +1 to +6 or -1 to -20, which are considered part of the splice donor and splice acceptor sites (PMID: 37352859).
SpliceAI predicts possible splice impact for this variant (max delta score = 0.49).
9 paper records listed. 5 cited in the classification.
In families 10683 and 2915, a G to A transition was found at position 1032. This transition of the last base of codon 344 has already been described in 5 families. As in family 10738 above, it should not affect the encoded alanine; however, because it is the last base of the exon, it has been suggested to cause abnormal splicing, although this has not been demonstrated.
Location Results, Molecular Genetics; Discussion
Context Affected-family case observations, segregation analysis, and RT-PCR with sequencing of KCNQ1 transcripts from lymphoblastoid cell lines; the 1032 G>A transcripts showed loss of exons 6 and 7.
DNA sequencing identified a heterozygous guanine to adenine change in KCNQ1 at nucleotide 1032 (c.1032G>A)
Location Results, sections 3.1–3.6; Discussion, sections 4.1–4.3
Context Three unrelated long-QT-syndrome families; six affected individuals; peripheral-blood leukocyte RT-PCR and real-time RT-PCR; heterologous expression in Xenopus laevis oocytes with two-electrode voltage clamp; GFP confocal microscopy and CFP/YFP FRET in COS7 cells.
In addition to c.1032GNA mutation, IVS7 +3ANG generates exon-skipping mRNAs, and thereby causing LQT1 phenotype.
Location Abstract; Introduction; Results sections 3.3–3.7; Discussion sections 4.1–4.3; Fig. 4 and Fig. 5
Context KCNQ1 exon 7 minigene splicing assays in COS7 cells, with confirmation in CHO and HL-1 cells; RT-PCR and real-time RT-PCR of patient lymphocyte RNA; Xenopus laevis oocyte two-electrode voltage-clamp recordings with KCNE1; one-dimensional human ventricular computer simulations; nine probands from nine unrelated families carrying c.1032G>A.
Compound heterozygous mutations c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) were identified in the proband. His daughter, who displayed a RWS phenotype, inherited c.1032G>A (p.Ala344Alasp) from him and novel missense mutation c.574C>T (p.Arg192Cys) from her mother who was a silent mutation carrier.
Location Results, Clinical characteristics and mutation finding in Family L151; Figure 4; Discussion
Context Three Chinese Jervell and Lange-Nielsen syndrome kindreds with PCR/direct sequencing, family genotyping, and comparison against 100 control alleles.
We identified seven aberrant RNA variants in A344Aspl-hiPSC-CMs, more complex compared with those in the peripheral lymphocytes.
Location Results: Clinical phenotypes and genetic analysis; Complex aberrant RNA splicing was observed in KCNQ1-A344Aspl hiPSC-CMs; electrophysiology sections
Context Patient-derived KCNQ1-A344Aspl hiPSCs differentiated into cardiomyocytes; KCNQ1 exon 5–10 cDNA cloning and quantitative RT-PCR for splice variants; multi-electrode-array field-potential recordings; perforated patch-clamp action-potential recordings; comparison with healthy control hiPSC-cardiomyocytes.
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.
This variant is present in gnomAD v4.1 (AF= 1.24288e-06; MAF= 0.00012%, 2/1609160 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.70116e-06; MAF= 0.00017%, 2/1175668 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.98111e-06; MAF= 0.00040%, 1/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80887e-06; MAF= 0.00088%, 1/113522 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (15 clinical laboratories) and as Pathogenic by ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3135)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.49).
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.