Variant: NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)

CA005255

52955 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 890c0acf-4509-4358-913b-ba54b0dde6b7

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.1096C>T
NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)
NC_000011.10:g.2585275C>T
CM000673.2:g.2585275C>T
NC_000011.9:g.2606505C>T
CM000673.1:g.2606505C>T
NC_000011.8:g.2563081C>T
NG_008935.1:g.145285C>T
ENST00000496887.7:c.771+1730C>T
ENST00000646564.2:c.588+1730C>T
ENST00000155840.12:c.1096C>T
ENST00000335475.6:c.715C>T
ENST00000646564.1:c.234+1730C>T
ENST00000155840.9:c.1096C>T
ENST00000335475.5:c.715C>T
NM_000218.2:c.1096C>T
NM_181798.1:c.715C>T

Likely Pathogenic

• Met criteria codes: PS4 PM2_Supporting PP3

• Not Met criteria codes: PM5 BS3 PS3 PP1 PP4

Expert Panel

Potassium Channel Arrhythmia VCEP

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

Evidence submitted by expert panel

Potassium Channel Arrhythmia VCEP

NM_000218.3(KCNQ1):c.1096C>T is a missense variant that causes substitution of arginine with tryptophan at position 366. This variant is present in gnomAD v.4.0.0 at a maximum allele frequency of 0.0000008993, with 1 allele / 1111974 total alleles in the European non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is rare and has been reported in 7 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 29497013, PMID: 24606995, PMID: 9693036, PMID: 26063740, PMID: 24363352, PMID: 19841300). The computational predictor REVEL gives a score of 0.921, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family, however, each affected family member lacks the confirmation of the Schwartz score >3.5 or QTc >480ms or syncope necessary to be included / counted for the PP1 code (PMID: 21499742). This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 29497013). This variant has been shown to disrupt KCNQ1 function in one experimental assay, manual patch clamp (PMID: 16556865), and shown not to disrupt KCNQ1 function in another experimental assay, the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), which has generated a prediction of normal effects of the mutant on IKs_classification, V1/2_classification, act_classification, and deact_classification (PMID: 29021305), so neither PS3_Supporting nor BS3_Supporting were met. 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: PS4, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• PS4: This variant is rare and has been reported in 6 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 29497013, PMID: 24606995, PMID: 9693036, PMID: 26063740, PMID: 24363352, PMID: 19841300).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0000008993, with 1 allele / 1111974 total alleles in the European non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.921, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The computational splicing predictor SpliceAI gives a score of 0.07 for donor 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.

Not Met criteria codes

• PM5: Three other missense variants in the same codon, NM_000218.3(KCNQ1):c.1097G>A (p.Arg366Gln), NM_000218.3(KCNQ1):c.1097G>T (p.Arg366Leu), and NM_000218.3(KCNQ1):c.1097G>C (p.Arg366Pro), have been reported in association with long QT syndrome 1. However, this position is not conserved across other KCNQ paralogues, so PM5 cannot be considered.
• BS3: This variant has been shown to disrupt KCNQ1 function in one experimental assay, manual patch clamp (PMID: 16556865), and shown not to disrupt KCNQ1 function in another experimental assay, the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), which has generated a prediction of normal effects of the mutant on IKs_classification, V1/2_classification, act_classification, and deact_classification (PMID: 29021305), so neither PS3_Supporting nor BS3_Supporting were met.
• PS3: This variant has been shown to disrupt KCNQ1 function in one experimental assay, manual patch clamp (PMID: 16556865), and has a mixed impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), which has generated a prediction of a dysfunctional effect on V1/2_classification, act_classification, and deact_classification but normal effects of the mutant on IKs_classification, (PMID: 29021305). The two findings are not compatible, so PS3_Supporting is not met.
• PP1: The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family, however, each affected family member does not have confirmation of the Schwartz score >3.5 or QTc >480ms or syncope necessary to be included / counted for the PP1 code (PMID: 21499742).
• PP4: This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 29497013).