Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000218.3(KCNQ1):c.328G>A (p.Val110Ile)

CA006800

53034 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e12d310f-55a9-4800-a044-32a63d018ae4
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.328G>A
NM_000218.3(KCNQ1):c.328G>A (p.Val110Ile)
NC_000011.10:g.2445426G>A
CM000673.2:g.2445426G>A
NC_000011.9:g.2466656G>A
CM000673.1:g.2466656G>A
NC_000011.8:g.2423232G>A
NG_008935.1:g.5436G>A
ENST00000496887.7:c.67G>A
ENST00000646564.2:c.328G>A
ENST00000155840.12:c.328G>A
ENST00000155840.9:c.328G>A
ENST00000345015.4:n.105G>A
ENST00000496887.6:c.67G>A
NM_000218.2:c.328G>A
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Uncertain Significance

Not Met criteria codes 9
PS3 PP1 PP3 PM1 PM2 BS4 BS3 BS1 BP4

Evidence Links 4

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Potassium Channel Arrhythmia VCEP
NM_000218.3(KCNQ1):c.328G>A is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 110 (p.Val110Ile). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008307, with 98 alleles / 1,179,710 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. Functional studies have been performed on this variant (PMID: 21164565, 29532034, and 29021305) but do not meet VCEP criteria for PS3/BS3. The computational predictor REVEL gives a score of 0.562, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. 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: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025).
Not Met criteria codes
PS3
Publication PMID: 21164565 supports there is no trafficking defect, but suggest loss of function but evidence is not definitive. Additional publication PMID: 29532034 supports no destabilization of protein, but offers no new data regarding possible loss of function. This does not meet VCEP PS3 requirements due to lack of consistent significant data.
Manual patch clamp - Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. Figure 3: In the homozygous channels, V110I causes a reduction in current. Given the considerable heterogeneity in expression from cell to cell, you need to have large n-values to be confident about changes in current density, but no n-values are given so cannot judge on robustness of this result. Second, there are no data reported for heterozygous channels. Third, there is no formal analysis of whether there are any changes in channel gating. From the raw traces shown, there is a suggestion of slower activation but this would need to be quantified. Overall, there is a hint of loss of function but far from definitive evidence for loss of function. Figure 7: Trafficking levels for WT and V110I are not different – suggests no trafficking defect PubMed:21164565
Variant, IKs_classification, V1/2_classification, act_classification, deact_classification, confidence score_Iks, confidence score_V1/2, confidence score_act, confidence score_deact V110I, Normal, Normal, Normal, Normal, 81.5, 61.5, 83.0, 68.0 All predicted normal PubMed:29021305
Classified as Normal or higher surface trafficking levels, but low peak current density with a dysfunctional channel. Flow cytometry was within normal total expression (normal cell surface expression). Exhibit maximal channel conductance ≤65% of WT Figure 1: V110I has normal trafficking (consistent with that reported by Codeiro et al.) Figure 4: NMR spectrum differences consistent with presence of a mutation (hence shifts in peaks) but they claim that it is not destabilised. Again consistent with no destablisation of protein They did not undertake any new electrophysiology studies – so the loss of function classification is based on the previous work from Codeiro listed above. PubMed:29532034
Computational model of induced pluripotent stem-cell derived cardiomyocytes for high throughput risk stratification -- the V110I variant had insufficient current density to optimize the IKs model PubMed:32797034
PP1
There are no primary literature reports with segregation data
PP3
The computational predictor REVEL gives a score of 0.562, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and does not strongly predict a damaging effect on KCNQ1 splicing.
PM1
Does not meet PM2 supporting, therefore cannot be met
PM2
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008307, with 98 alleles / 1,179,710 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met.
BS4
There are no primary literature reports with segregation data
BS3
The study PMID: 29021305 supports no functional impact of this variant. However, this publication can only be considered preliminary evidence without additional supporting papers. This does not meet VCEP requirements for BS3.
Manual patch clamp - Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. Figure 3: In the homozygous channels, V110I causes a reduction in current. Given the considerable heterogeneity in expression from cell to cell, you need to have large n-values to be confident about changes in current density, but no n-values are given so cannot judge on robustness of this result. Second, there are no data reported for heterozygous channels. Third, there is no formal analysis of whether there are any changes in channel gating. From the raw traces shown, there is a suggestion of slower activation but this would need to be quantified. Overall, there is a hint of loss of function but far from definitive evidence for loss of function. Figure 7: Trafficking levels for WT and V110I are not different – suggests no trafficking defect PubMed:21164565
Variant, IKs_classification, V1/2_classification, act_classification, deact_classification, confidence score_Iks, confidence score_V1/2, confidence score_act, confidence score_deact V110I, Normal, Normal, Normal, Normal, 81.5, 61.5, 83.0, 68.0 All predicted normal PubMed:29021305
Classified as Normal or higher surface trafficking levels, but low peak current density with a dysfunctional channel. Flow cytometry was within normal total expression (normal cell surface expression). Exhibit maximal channel conductance ≤65% of WT Figure 1: V110I has normal trafficking (consistent with that reported by Codeiro et al.) Figure 4: NMR spectrum differences consistent with presence of a mutation (hence shifts in peaks) but they claim that it is not destabilised. Again consistent with no destablisation of protein They did not undertake any new electrophysiology studies – so the loss of function classification is based on the previous work from Codeiro listed above. PubMed:29532034
Computational model of induced pluripotent stem-cell derived cardiomyocytes for high throughput risk stratification -- the V110I variant had insufficient current density to optimize the IKs model PubMed:32797034
BS1
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008307, with 98 alleles / 1,179,710 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met.
BP4
The computational predictor REVEL gives a score of 0.562, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and does not strongly predict a damaging effect on KCNQ1 splicing.
Curation History
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