NM_000219.6:c.227_229delACCinsTCTA

Variant names:

• chr21-34449406-GGT-TAGA
• rs1555843898
• NM_000219.6:c.227_229delACCinsTCTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000219.6(KCNE1):​c.227_229delACCinsTCTA​(p.Asp76ValfsTer35) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D76D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 NM_000219.6 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.49
• Publications: 0 publications found

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]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 6 pathogenic variants in the truncated region.
• PP5: Variant 21-34449406-GGT-TAGA is Pathogenic according to our data. Variant chr21-34449406-GGT-TAGA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 441101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	NM_000219.6	MANE Select	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 17

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Dec 11, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19716085)

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Long QT syndrome Pathogenic:1

Nov 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Asp76Valfs*35) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the KCNE1 protein. This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (Invitae). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Arg98Trp) have been determined to be pathogenic (PMID: 16922724, 17341399, 19907016, 30530868). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

Cardiovascular phenotype Pathogenic:1

Jul 07, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227_229delACCinsTCTA pathogenic mutation, located in coding exon 1 of the KCNE1 gene, results from the deletion of 3 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.D76Vfs*35). This alteration occurs at the 3' terminus of theKCNE1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 42% of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function and affects a significant portion of the protein (Ambry internal data). This variant was reported in individual(s) from a cohort referred for long QT syndrome genetic testing (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=1/199	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1555843898; hg19: chr21-35821704;