rs1131691762

Positions:

• chr21-34449622-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000219.6(KCNE1):​c.12_13insT​(p.Asn5Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -4.43

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PP5: Variant 21-34449622-T-TA is Pathogenic according to our data. Variant chr21-34449622-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 430060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.12_13insT	p.Asn5Ter	frameshift_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.12_13insT	p.Asn5Ter	frameshift_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251142 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000263 AC: 2 AN: 761030 Hom.: 0 Cov.: 10 AF XY: 0.00000254 AC XY: 1 AN XY: 392938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000392

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 13

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2015	The c.12dupT variant in the KCNE1 gene has been observed in an individual referred for LQTS testing and was absent from over 2,600 reference alleles (Kapplinger et al., 2009). This variant causes a shift in reading frame starting at codon Asparagine 5, which creates a premature stop codon at this position of the new reading frame, denoted p.N5X. This pathogenic variant is expected to result in an abnormal, truncated protein product. Other frameshift variants in the KCNE1 gene have been reported in HGMD in association with arrhythmia (Stenson et al., 2014). Furthermore, the c.12dupT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.12dupT in the KCNE1 gene is interpreted as a pathogenic variant. -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

This sequence change creates a premature translational stop signal (p.Asn5*) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the KCNE1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with long-QT syndrome (PMID: 19716085). This variant is also known as 13insT. ClinVar contains an entry for this variant (Variation ID: 430060). This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Asp76Asn) have been determined to be pathogenic (PMID: 9354802, 24400172, 24606995). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.12dupT pathogenic mutation, located in coding exon 1 of the KCNE1 gene, results from a duplication of T at nucleotide position 12, causing a translational frameshift with a predicted alternate stop codon (p.N5*). This variant has been reported in several long QT and/or Jervell and Lange-Nielsen syndrome cohorts, but clinical information was limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Faridi R et al. Hum Mutat, 2019 Feb;40:162-176; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Roberts JD et al. Circulation, 2020 Feb;141:429-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. However, pathogenic and likely pathogenic KCNE1 variants typically exhibit low penetrance in the heterozygous state and may represent risk factors that manifest clinically only in the presence of additional genetic or environmental factors (Roberts JD et al. Circulation. 2020 02;141(6):429-439). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131691762; hg19: chr21-35821920;