rs1555843898

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Sel.	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	P15382
	KCNE1	NM_001127668.4		c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	NP_001121141.1	C7S316

Ensembl Transcripts

Sel.	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	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.227_229delACCinsTCTA	p.Asp76ValfsTer35	frameshift missense	Exon 2 of 2	ENSP00000416258.2	P15382

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome (1)
1	-	-	not provided (2)

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;