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.477+1G>A

CA007168

200874 (ClinVar)

Gene: KCNQ1
Condition: long QT syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3d01767e-ace7-4d3c-a2fa-784c6d510098
Approved on: 2025-07-01
Published on: 2025-07-02

HGVS expressions

NM_000218.3:c.477+1G>A
NM_000218.3(KCNQ1):c.477+1G>A
NC_000011.10:g.2528019G>A
CM000673.2:g.2528019G>A
NC_000011.9:g.2549249G>A
CM000673.1:g.2549249G>A
NC_000011.8:g.2505825G>A
NG_008935.1:g.88029G>A
ENST00000496887.7:c.216+1G>A
ENST00000646564.2:c.477+1G>A
ENST00000155840.12:c.477+1G>A
ENST00000335475.6:c.96+1G>A
ENST00000646564.1:c.123+1G>A
ENST00000155840.9:c.477+1G>A
ENST00000335475.5:c.96+1G>A
ENST00000496887.6:c.216+1G>A
NM_000218.2:c.477+1G>A
NM_181798.1:c.96+1G>A
More

Likely Pathogenic

Met criteria codes 2
PP4 PVS1
Not Met criteria codes 6
BA1 PM3 PM2 BS1 PS4 PS3

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.477+1G>A is a splicing variant predicted to cause out-of-frame skipping of exon 2, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds, congenital deafness and a swimming-associated event, which together are highly specific for long QT syndrome 1 (PP4; PMID:16987820). This variant has been reported in homozygosity in one proband with Jervell and Lange-Nielsen syndrome that was reported to have both a long QT interval and congenital deafness (PMID: 16987820), however PM3_Supporting is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). This variant has been shown to disrupt KCNQ1 function in two required experimental assays, including RNA Metabolism and automated patch clamp (PMID: 16987820), however, PS3_Supporting is not met since the variant has already met PVS1. In summary, this variant has been classified as likely pathogenic for long QT syndrome 1 according to the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel: PVS1 and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025).
Met criteria codes
PP4
This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds and a swimming-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID: 16987820).
PVS1
This variant occurs at a canonical splice site in intron 2 and is expected to disrupt splicing and trigger an exon-skipping event introducing a premature stop codon that is predicted to lead to nonsense-mediated decay (PVS1).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
This variant has been reported in homozygosity in one proband with Jervell and Lange-Nielsen syndrome that was reported to have both a long QT interval and congenital deafness (PMID: 16987820), however PM3_Supporting is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting).
PM2
This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001359, with 16 alleles / 1177494 total alleles in the European (non-Finnish) 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 0.00001359, with 16 alleles / 1177494 total alleles in the European (non-Finnish) 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 is rare and has been reported in 1 proband affected with long QT syndrome 1, however, the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met (PMID: 15466642). Additionally, the PM3 code, which is mutually exclusive with PS4, is being applied in this curation.
PS3
This variant has been shown to disrupt KCNQ1 function in two required experimental assays, including  RNA Metabolism and automated patch clamp (PMID: 16987820). PS3_Supporting is not met since the variant has already met PVS1.
RT-PCR of total RNA from blood cells (lymphocytes) of healthy and affected individuals shows the wild type (277 bp) and the mutant (186 bp) fragments in heterozygous subjects (lane II.1, II.2, II.3, and I.1). Symptomatic patients selectively amplify the mutant fragment (lanes III.1 and III.2), while inconspicuous family members (lane I.2) selectively amplify the wild type fragment. PubMed:16987820
Curation History
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