rs281865421

Variant names:

• chr21-34449458-CAGGGT-AGGGGG
• rs281865421
• NM_000219.6:c.172_177delACCCTGinsCCCCCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_000219.6(KCNE1):​c.172_177delACCCTGinsCCCCCT​(p.ThrLeu58ProPro) variant causes a missense change. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001417840: Experimental studies have shown that this variant affects KCNE1 function (PMID:11530100, 19907016)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.68
• Publications: 1 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001417840: Experimental studies have shown that this variant affects KCNE1 function (PMID: 11530100, 19907016).; SCV001822422: Published functional studies demonstrate that the p.(T58P)/p.(L59P) variant severely weakens the interaction of KCNE1 with KCNQ1 and leads to an inability to modulate channel gating and the production of currents that lack the slow activation profile (PMID: 19907016)
• PP5: Variant 21-34449458-CAGGGT-AGGGGG is Pathogenic according to our data. Variant chr21-34449458-CAGGGT-AGGGGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13475.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.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	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.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.172_177delACCCTGinsCCCCCT	p.ThrLeu58ProPro	missense	N/A	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: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Jervell and Lange-Nielsen syndrome 2 (1)
1	-	-	Long QT syndrome (1)
1	-	-	Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=0/200	disease causing

Splicing

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

Other links and lift over

dbSNP: rs281865421; hg19: chr21-35821756;