Variant: NM_000218.3(KCNQ1):c.458C>T (p.Thr153Met)

CA007144

67075 (ClinVar)

Gene: KCNQ1

Condition: long QT syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 3315d9b1-5d3f-4d40-9b2c-e332ce84d9f2

Approved on: 2025-07-01

Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.458C>T
NM_000218.3(KCNQ1):c.458C>T (p.Thr153Met)
NC_000011.10:g.2527999C>T
CM000673.2:g.2527999C>T
NC_000011.9:g.2549229C>T
CM000673.1:g.2549229C>T
NC_000011.8:g.2505805C>T
NG_008935.1:g.88009C>T
ENST00000496887.7:c.197C>T
ENST00000646564.2:c.458C>T
ENST00000155840.12:c.458C>T
ENST00000335475.6:c.77C>T
ENST00000646564.1:c.104C>T
ENST00000155840.9:c.458C>T
ENST00000335475.5:c.77C>T
ENST00000496887.6:c.197C>T
NM_000218.2:c.458C>T
NM_181798.1:c.77C>T

Likely Benign

• Met criteria codes: BS1 BP5

• Not Met criteria codes: BS3 BP4 PP3 BA1 PM2 PM1

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.458C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 153 (p.Thr153Met). This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific. The patient has a KCNH2 variant, p.Arg752Trp, that is P/LP in ClinVar. (BP5; PMID: 28794082). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0006396, with 48 alleles / 75052 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 (BS1). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BP5, BS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

Met criteria codes

• BS1: This variant is present in gnomAD v.4.0.0 at a maximum allele frequency of 0.0006396, with 48 alleles / 75052 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 (BS1).
• BP5: This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific. The patient has a KCNH2 variant, p.Arg752Trp, that is P/LP in ClinVar (BP5; PMID: 28794082).

Not Met criteria codes

• BS3: PMID: 30571187 contains an automated patch clamp assay with this variant, but it does not meet BS3 criteria.
• BP4: The computational predictor REVEL gives a score of 0.739, 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.
• PP3: The computational predictor REVEL gives a score of 0.739, 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 for donor and acceptor gain and loss, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant is not a missense substitution within the pore helix consisting of amino acids 300 to 320, which is a well-characterized functional domain required for the channel function and selectivity filter of KCNQ1 (PMID: 15649981), and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD.