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.514G>A (p.Val172Met)

CA007311

67078 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2c99b4b4-6af2-4def-b68c-4d9a25c854f5
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.514G>A
NM_000218.3(KCNQ1):c.514G>A (p.Val172Met)
NC_000011.10:g.2570664G>A
CM000673.2:g.2570664G>A
NC_000011.9:g.2591894G>A
CM000673.1:g.2591894G>A
NC_000011.8:g.2548470G>A
NG_008935.1:g.130674G>A
ENST00000496887.7:c.253G>A
ENST00000646564.2:c.478-12771G>A
ENST00000155840.12:c.514G>A
ENST00000335475.6:c.133G>A
ENST00000646564.1:c.124-12771G>A
ENST00000155840.9:c.514G>A
ENST00000335475.5:c.133G>A
ENST00000496887.6:c.253G>A
NM_000218.2:c.514G>A
NM_181798.1:c.133G>A
More

Benign

Met criteria codes 3
BS3_Supporting BS4 BS1
Not Met criteria codes 7
PS4 BP4 BP2 BP5 PP4 PP3 PM3

Evidence Links 0

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.514G>A is a missense variant that substitutes valine with methionine at codon 172 (p.Val172Met). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001317, with 12 alleles / 91,084 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001 (BS1). At least two patients affected with long QT syndrome have been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID: 28944242, PMID: 28438721). However, PM3 is not met because the variant is not sufficiently rare. The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 2 affected members (PMID: 28438721; BS4). This variant has been observed in at least 2 probands with a possible alternate molecular basis for disease, however, the alternative variants are located within KCNQ1 itself and the phenotype does not match another form of LQTS, so this evidence is not considered eligible for the BP5 code (PMID: 28944242, PMID: 28438721). Exogenously expressed KCNQ1 harboring this variant has an IKs of 1.117 (expressed as a fraction of the wild-type), which indicates higher-than-wild-type activity within the near-normal range (PMID: 30571187). The Meiler Lab functional impact predictor gave this variant a classification of normal for IKs, V1/2_classification, Tau of activation, and Tau of deactviation, consistent with benign impact on the protein product (PMID: 29021305, BS3_Moderate). In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BS1, BS4, and BS3_Moderate. (VCEP specifications version 1.0.0; date of approval 03/04/2025).
Met criteria codes
BS3_Supporting
Exogenously expressed KCNQ1 harboring this variant has an IKs of 1.117 (expressed as a fraction of the wild-type), which indicates higher-than-wild-type activity within the near-normal range (PMID: 30571187, supplementary data set file). In addition, the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) gave this variant an IKs_classification of normal (confidence score 85.0), V1/2_classification of normal (confidence score 61.5), act_classification of normal (confidence score 79.0), and deact_classification of normal (confidence score 68.5). These confidence scores are all above the thresholds for high confidence scores (>57 for IKs, > 55 for V1/2, >59 for tau_act, and >59 for tau_deact) (PMID: 29021305, BS3_Moderate).
BS4
The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 2 affected members (PMID: 28438721; BS4).
BS1
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001317, with 12 alleles / 91,084 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001 (BS1).
Not Met criteria codes
PS4
This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds and syncope with unknown trigger, are sufficient for inclusion in PS4 proband counting (PMID: 28944242). However, the variant has met the BA1 threshold and is not sufficiently rare to consider the PS4 code.
BP4
The computational predictor REVEL gives a score of 0.71, which is above the ClinGen Potassium Channel Arrhythmia VCEP 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 all splicing types, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing.
BP2
A patient affected with long QT syndrome (but without deafness) has been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID: 28944242). BP2 is not met because this criterion is not considered applicable for long QT syndrome 1.
BP5
This variant has been observed in at least 2 probands with a possible alternate molecular basis for disease, however, the alternative variants are located within KCNQ1 itself and the phenotype does not match another form of LQTS, so this evidence is not considered eligible for the BP5 code (PMID: 28944242, PMID: 28438721).
PP4
This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds and syncope with unknown trigger, which together are not sufficiently specific to meet PP4 for long QT syndrome 1 (PMID: 28944242).
PP3
The computational predictor REVEL gives a score of 0.71, which is below the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of >0.75 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00 for all splicing types, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing.
PM3
A patient affected with long QT syndrome (but without deafness) has been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID: 28944242). PM3 is not met because the variant meets BA1 and is not sufficiently rare.
Curation History
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