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.860C>A (p.Ala287Glu)

CA008494

53118 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1dcfefe3-fe28-4afc-9ef7-edca73564585
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.860C>A
NM_000218.3(KCNQ1):c.860C>A (p.Ala287Glu)
NC_000011.10:g.2572925C>A
CM000673.2:g.2572925C>A
NC_000011.9:g.2594155C>A
CM000673.1:g.2594155C>A
NC_000011.8:g.2550731C>A
NG_008935.1:g.132935C>A
ENST00000496887.7:c.599C>A
ENST00000646564.2:c.478-10510C>A
ENST00000155840.12:c.860C>A
ENST00000335475.6:c.479C>A
ENST00000646564.1:c.124-10510C>A
ENST00000155840.9:c.860C>A
ENST00000335475.5:c.479C>A
NM_000218.2:c.860C>A
NM_181798.1:c.479C>A
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Uncertain Significance

Met criteria codes 2
BS3_Supporting PP3
Not Met criteria codes 5
PM5 PM2 BS1 PS4 PP4

Evidence Links 2

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.860C>A is a missense variant that replaces alanine with glutamic acid at codon 287. Three missense variants in the same codon, NM_000218.3(KCNQ1):c.859G>T (p.Ala287Ser), NM_000218.3(KCNQ1):c.859G>A (p.Ala287Thr), and NM_000218.3(KCNQ1):c.860C>T (p.Ala287Val), have been reported in association with long QT syndrome (PMID: 23631430, SCV004024206.1, SCV003288475.1) but have not yet been classified for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008334, with 5 alleles / 59,998 total alleles in the Admixed American 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 one affected proband with a diagnosis of long QT syndrome, with confirmation of a prolonged QTc interval (PMID: 16414944), however, the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met. Available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 16414944). The computational predictor REVEL gives a score of 0.847, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to have a non-deleterious impact on KCNQ1 function in a manual patch-clamp assay (PMID:28491751; BS3_Supporting). Also, 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 19.5), V1/2_classification of normal (confidence score 19.5), act_classification of normal (confidence score 51.0), and deact_classification of normal (confidence score 51.0). These confidence scores are all below the thresholds for high confidence scores (>57 for IKs, > 55 for V1/2, >59 for tau_act, and >59 for tau_deact) (PMID: 29021305). 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: BS3_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).
Met criteria codes
BS3_Supporting
This variant has been shown to have a non-deleterious impact on KCNQ1 function in a manual patch-clamp assay (PMID:28491751; BS3_Supporting). Also, 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 19.5), V1/2_classification of normal (confidence score 19.5), act_classification of normal (confidence score 51.0), and deact_classification of normal (confidence score 51.0). These confidence scores are all below 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_Supporting).
This variant has been shown to have a non-deleterious impact on KCNQ1 function in a Manual patch-clamp assay when expressed in Xenopus oocytes either alone (170% of wild-type) or with KCNE1 (~95-100% of wild-type) (Figures 3B, 3D; PMID:28491751; BS3_Supporting). PubMed:28491751
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 19.5), V1/2_classification of normal (confidence score 19.5), act_classification of normal (confidence score 51.0), and deact_classification of normal (confidence score 51.0). These confidence scores are all below the thresholds for high confidence scores (>57 for IKs, > 55 for V1/2, >59 for tau_act, and >59 for tau_deact) (PMID: 29021305). PubMed:29021305
PP3
The computational predictor REVEL gives a score of 0.847, 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 0.06 for donor gain, 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 missense variants in the same codon, NM_000218.3(KCNQ1):c.859G>T (p.Ala287Ser), NM_000218.3(KCNQ1):c.859G>A (p.Ala287Thr), and NM_000218.3(KCNQ1):c.860C>T (p.Ala287Val), have been reported in association with long QT syndrome (PMID: 23631430, SCV004024206.1, SCV003288475.1) but have not yet been classified for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met.
PM2
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008334, with 5 alleles / 59,998 total alleles in the Admixed American 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.
BS1
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008334, with 5 alleles / 59,998 total alleles in the Admixed American 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.
PS4
This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, with confirmation of a prolonged QTc interval (PMID: 16414944), however, the requirement for 2 unrelated has not been reached so the PS4_Supporting code is not yet met. In addition, in order to be evaluated for this criterion, the variant must not meet BS1.
PP4
This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 16414944).
Curation History
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