rs281865421

chr21-34449458-CAGGGT-AGGGGG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_000219.6(KCNE1):c.172_177delinsCCCCCT(p.Thr58_Leu59delinsProPro) variant causes a missense change. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Likely benign.

• 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

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000219.6
• 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 id is 13475.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.172_177delinsCCCCCT	p.Thr58_Leu59delinsProPro	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.172_177delinsCCCCCT	p.Thr58_Leu59delinsProPro	missense_variant	4/4	1	NM_000219.6	P1

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: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2022

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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 (Harmer et al., 2010); This variant is associated with the following publications: (PMID: 11530100, 11692163, 26410412, 9328483, 19907016, 31941373) -

Jervell and Lange-Nielsen syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1997

- -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This variant, c.172_177delinsCCCCCT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the KCNE1 protein (p.Thr58_Leu59delinsProPro). This variant is present in population databases (rs147187721, gnomAD 0.002%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 9328483, 10973849, 31941373). It has also been observed to segregate with disease in related individuals. This variant is also known as T59P/L60P. ClinVar contains an entry for this variant (Variation ID: 132658). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNE1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 11530100, 19907016). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865421; hg19: chr21-35821756;