21-34449477-A-G

Variant names:

• chr21-34449477-A-G
• rs199473355
• NM_000219.6:c.158T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000219.6(KCNE1):​c.158T>C​(p.Phe53Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F53L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 16)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.89
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 98 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

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.158T>C	p.Phe53Ser	missense	Exon 4 of 4	NP_000210.2
	KCNE1	NM_001127668.4		c.158T>C	p.Phe53Ser	missense	Exon 3 of 3	NP_001121140.1
	KCNE1	NM_001127669.4		c.158T>C	p.Phe53Ser	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.158T>C	p.Phe53Ser	missense	Exon 4 of 4	ENSP00000382226.2
	KCNE1	ENST00000399289.7	TSL:1	c.158T>C	p.Phe53Ser	missense	Exon 3 of 3	ENSP00000382228.3
	KCNE1	ENST00000416357.6	TSL:1	c.158T>C	p.Phe53Ser	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 16

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.43		Loss of stability (P = 0.0668)
MVP		0.98
MPC		0.57
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.21
gMVP		0.83
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199473355; hg19: chr21-35821775;