rs74315445

Variant names:

• chr21-34449409-C-T
• rs74315445
• NM_000219.6:c.226G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP3 PP5

The NM_000219.6(KCNE1):​c.226G>A​(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,598,798 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000238442: Available functional studies in Xenopus laevis oocytes and in Chinese hamster ovaries indicate a reduced function for this variant relative to wild type. PMID:11874988, 12566567" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00013 (3 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:25 U:1 O:1
• Conservation: PhyloP100: 5.04
• Publications: 60 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238442: Available functional studies in Xenopus laevis oocytes and in Chinese hamster ovaries indicate a reduced function for this variant relative to wild type. PMID:11874988, 12566567; SCV000839962: Functional studies have indicated that the p.Asp76Asn variant KCNE1 protein has altered activity (PMID: 10400998, 10428953, 11874988, 12566567).; SCV005398184: "Functional studies using patch clamp technique showed reduced potassium current and accelerated channel deactivation rates in multiple cell types with the variant (PMIDs: 9354802, 19340287, 24400172)."; SCV000711386: "In vitro functional studies provide some evidence that the p.Asp76Asn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 2008, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not accurately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001)."; SCV000278993: Published functional studies demonstrate a damaging effect as this variant leads to a dominant-negative loss of channel function (Splawski et al., 1997; Hoppe et al., 2001; Chen et al., 2009; Du et al., 2013); SCV001474376: Functional studies suggest this variant leads to altered potassium channel activity, including reduced current and faster deactivation (Kurokawa 2003, Splawski 1997).; SCV000319991: "In vitro assays have reported that the p.D76N alteration impairs ion channel function by altering voltage dependence and suppressing current through KCNQ1 and KCNH2-associated channels (Kurokawa J et al. Proc. Natl. Acad. Sci. U.S.A. 2003; 100(4):2122-7; Abbott GW et al. FASEB J. 2002; 16(3):390-400; Bianchi L et al. Hum. Mol. Genet. 1999; 8(8):1499-507)."; SCV000549148: Experimental studies have shown that this missense change affects KCNE1 function (PMID: 9354802, 10400998, 10428953, 11874988, 12566567, 24400172).; SCV005045721: Functional studies have indicated that the p.Asp76Asn variant KCNE1 protein has altered activity (PMID: 10400998, 10428953, 11874988, 12566567).; SCV000711385: "In vitro functional studies provide some evidence that the p.Asp76Asn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 2008, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not accurately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001)."; SCV005888507: Several publications report experimental evidence evaluating an impact on protein function and found that the most pronounced variant effect impairs channel function in both the homozygous and heterozygous states (e.g. Splawski_1997, Chen_2009, Haitin_2009). The following publications have been ascertained in the context of this evaluation (PMID: 9354783, 9354802, 15840476, 19716085, 9445165, 19521339, 24606995, 19340287).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• PP5: Variant 21-34449409-C-T is Pathogenic according to our data. Variant chr21-34449409-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13477.

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.226G>A	p.Asp76Asn	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.226G>A	p.Asp76Asn	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.226G>A	p.Asp76Asn	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.226G>A	p.Asp76Asn	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.226G>A	p.Asp76Asn	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.226G>A	p.Asp76Asn	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.0000565 AC: 8 AN: 141658 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000934

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251386 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1457140 Hom.: 3 Cov.: 29 AF XY: 0.000114 AC XY: 83 AN XY: 725178

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000160 AC: 177 AN: 1107588

Other (OTH) AF: 0.0000498 AC: 3 AN: 60278

GnomAD4 genome AF: 0.0000565 AC: 8 AN: 141658 Hom.: 0 Cov.: 17 AF XY: 0.0000146 AC XY: 1 AN XY: 68600

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000520 AC: 2 AN: 38484

American (AMR) AF: 0.00 AC: 0 AN: 13982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 4620

South Asian (SAS) AF: 0.00 AC: 0 AN: 4256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000934 AC: 6 AN: 64262

Other (OTH) AF: 0.00 AC: 0 AN: 1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0412655), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Long QT syndrome 5 (6)
4	-	-	Long QT syndrome (4)
2	-	-	Jervell and Lange-Nielsen syndrome (2)
2	-	-	Jervell and Lange-Nielsen syndrome 2 (2)
-	1	-	Arrhythmogenic right ventricular cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital long QT syndrome (2)
1	-	-	Jervell and Lange-Nielsen syndrome 1 (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Benign	0.086	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.59
MVP		0.96
MPC		0.37
ClinPred		0.49	T
GERP RS		5.2
Varity_R		0.21
gMVP		0.85
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs74315445; hg19: chr21-35821707;