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.674C>T (p.Ser225Leu)

CA007870

53083 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d110d5f8-3915-4471-91db-63e40f63e513
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.674C>T
NM_000218.3(KCNQ1):c.674C>T (p.Ser225Leu)
NC_000011.10:g.2571394C>T
CM000673.2:g.2571394C>T
NC_000011.9:g.2592624C>T
CM000673.1:g.2592624C>T
NC_000011.8:g.2549200C>T
NG_008935.1:g.131404C>T
ENST00000496887.7:c.413C>T
ENST00000646564.2:c.478-12041C>T
ENST00000155840.12:c.674C>T
ENST00000335475.6:c.293C>T
ENST00000646564.1:c.124-12041C>T
ENST00000155840.9:c.674C>T
ENST00000335475.5:c.293C>T
ENST00000496887.6:c.413C>T
NM_000218.2:c.674C>T
NM_181798.1:c.293C>T
More

Likely Pathogenic

Met criteria codes 3
PS3 PS4 PP3
Not Met criteria codes 6
PVS1 PM1 PM2 BA1 BS3 BS1

Evidence Links 5

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.674C>T is a missense variant predicted to cause a substitution of serine with leucine at amino acid 225 (p.Ser225Leu). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001098, with 1 allele / 91,080 total alleles in the South Asian 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. This variant has been reported in at least 11 unrelated individuals with LQTS (PS4; PMID: 22885918, 19841300, 17470695, 15840476, 10973849, 15466642, 9927399). Functional studies have been performed on this variant and meet criteria for PS3 with 1 RNA observation and 4 electrophysiology study observations all demonstrating a damaging effect on the protein function (PS3; PMID: 29021305, 22456477, 21451124, 19590188, 11087258). Multiple lines of computational evidence (REVEL score 0.873) suggest this variant is likely to be disruptive (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).
Met criteria codes
PS3
Per KCNQ1 VCEP criteria, this variant meets 1 RNA observation and 4 electrophysiology study observations all demonstrating a damaging effect on the protein function -- this is consistent with Strong evidence for PS3
The variant is part of a data set confirming slow channel activation is associated with an increased risk of cardiac events -- additional information not available due to inability to access full paper PubMed:21451124
Detected at cell surface with dominant negative effect on wild-type IKs current - 1 independent consistent observation for electrophysiology testing PubMed:11087258
Altered voltage channel - 1 independent consistent observation for electrophysiology testing all mutants shifted the voltage dependence of activation to the right and reduced the voltage dependence of deactivation kinetics. The activation kinetics were differently affected in homomeric mutant channels compared to wild type KCNQ1. All three mutations reduced KCNQ1/KCNE1 channel currents in a dominant-negative manner when the mutants were coexpressed with wt subunits suggesting reduced I(Ks) as the molecular basis of LQT1. PubMed:19590188
S225L, Dysfunctional, Dysfunctional, Dysfunctional, Dysfunctional, 42.0, 86.5, 51.5, 67.5 Predicted damaging, meets VCEP criteria for electrophysiology study PubMed:29021305
Expression of wild-type and mutant subunits were confirmed by Western blot. Expression levels were not significantly decreased for the mutant subunits when compared to wild-type. -- RNA protein metabolism Measured channel basal function and regulation – decreased for S225L -- electrophysiology This counts for 2 observations per KCNQ1 VCEP criteria, 1 for RNA and 1 for electrophysiology PubMed:22456477
PS4
This variant has been reported in at least 11 unrelated individuals with LQTS, possibly more, data regarding family segregation in some published literature is unclear. However, there are extensive case reports of this variant. Per ClinGen KCNQ1 VCEP, PS4 is met with greater than or equal to 6 probands
PP3
The computational predictor REVEL gives a score of 0.873, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.1 for acceptor loss, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP threshold of >0.5 and does not strongly predict that the variant disrupts the splicing of KCNQ1 (PP3).
Not Met criteria codes
PVS1
not a truncating variant
PM1
Not in the pore helix Does not meet PM2
PM2
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001098, with 1 allele / 91080 total alleles in the South Asian 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.
BA1
The variant is present gnomAD v4.0 the maximum allele frequency is 1 in 86256 (South Asian), 0.0000115, or .0011%. The overall allele frequency is 5/1459266 or 0.0003426%. This is not met as it is no greater than the VCEP requirement of >0.001 (0.1%).
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The variant is present gnomAD v4.0 the maximum allele frequency is 1 in 86256 (South Asian), 0.0000115, or .0011%. The overall allele frequency is 5/1459266 or 0.0003426%. This is not met as it is not greater than the VCEP requirement of >0.0001 (0.01%).
Curation History
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