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.1831G>A (p.Asp611Asn)

CA006476

67059 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 95220edf-2b1c-4319-b341-b75c3057d060
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.1831G>A
NM_000218.3(KCNQ1):c.1831G>A (p.Asp611Asn)
NC_000011.10:g.2847803G>A
CM000673.2:g.2847803G>A
NC_000011.9:g.2869033G>A
CM000673.1:g.2869033G>A
NC_000011.8:g.2825609G>A
NG_008935.1:g.407813G>A
ENST00000496887.7:c.1474G>A
ENST00000155840.12:c.1831G>A
ENST00000335475.6:c.1450G>A
ENST00000526095.2:c.235G>A
ENST00000155840.9:c.1831G>A
ENST00000335475.5:c.1450G>A
ENST00000526095.1:n.338G>A
NM_000218.2:c.1831G>A
NM_181798.1:c.1450G>A
NR_130721.1:n.778-7361C>T
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Uncertain Significance

Not Met criteria codes 7
BP4 PM2 PS3 PS4 PM3 PP3 BS1

Evidence Links 1

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.1831G>A is a missense variant that causes replacement of aspartic acid with asparagine at position 611. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required phenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID: 19716085, PMID: 19862833, PMID: 22727609, PMID: 33614747). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 27917693). The computational predictor REVEL gives a score of 0.593, 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 BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing. The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID: 29021305), so PS3_Supporting is not met. 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
BP4
The computational predictor REVEL gives a score of 0.593, 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 BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing.
PM2
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met.
PS3
The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID: 29021305), so PS3_Supporting is not met.
The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID: 29021305). PubMed:29021305
PS4
This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required pxhenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID: 19716085, PMID: 19862833, PMID: 22727609, PMID: 33614747).
PM3
This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 27917693).
PP3
The computational predictor REVEL gives a score of 0.593, 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 >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing.
BS1
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met.
Curation History
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