rs199473645

Variant names:

• chr21-34449436-G-A
• rs199473645
• NM_000219.6:c.199C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34449436-G-A
• chr21-34449436-G-C
• chr21-34449436-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PP3_Moderate PP5

The NM_000219.6(KCNE1):​c.199C>T​(p.Arg67Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000262 in 1,528,300 control chromosomes in the GnomAD database, including 1 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: "SCV000320142: In a study looking at the function of phosphatidylinositol 4,5-biphosphate in potassium channel IKs, p.R67C was shown to cause a reduced current when compared to the wildtype (Li Y, Proc. Natl. Acad. Sci. U.S.A. 2011 May" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 O:1
• Conservation: PhyloP100: 6.70
• Publications: 15 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 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000320142: In a study looking at the function of phosphatidylinositol 4,5-biphosphate in potassium channel IKs, p.R67C was shown to cause a reduced current when compared to the wildtype (Li Y, Proc. Natl. Acad. Sci. U.S.A. 2011 May; 108(22):9095-100).; SCV000834200: Experimental studies have shown that this missense change affects KCNE1 function (PMID: 21576493).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 21-34449436-G-A is Pathogenic according to our data. Variant chr21-34449436-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132660.

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.199C>T	p.Arg67Cys	missense	Exon 4 of 4	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.199C>T	p.Arg67Cys	missense	Exon 3 of 3	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.199C>T	p.Arg67Cys	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.199C>T	p.Arg67Cys	missense	Exon 4 of 4	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.199C>T	p.Arg67Cys	missense	Exon 3 of 3	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.199C>T	p.Arg67Cys	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.0000374 AC: 5 AN: 133706 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000278

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: 0.0000654

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251382 AF XY: 0.0000294

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000251 AC: 35 AN: 1394594 Hom.: 1 Cov.: 26 AF XY: 0.0000330 AC XY: 23 AN XY: 696712

African (AFR) AF: 0.000124 AC: 4 AN: 32316

American (AMR) AF: 0.000136 AC: 6 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39290

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000181 AC: 19 AN: 1051786

Other (OTH) AF: 0.0000515 AC: 3 AN: 58224

GnomAD4 genome AF: 0.0000374 AC: 5 AN: 133706 Hom.: 0 Cov.: 17 AF XY: 0.0000155 AC XY: 1 AN XY: 64538

African (AFR) AF: 0.0000278 AC: 1 AN: 35950

American (AMR) AF: 0.00 AC: 0 AN: 13180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3088

East Asian (EAS) AF: 0.00 AC: 0 AN: 4276

South Asian (SAS) AF: 0.00 AC: 0 AN: 3912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000654 AC: 4 AN: 61184

Other (OTH) AF: 0.00 AC: 0 AN: 1754

Alfa AF: 0.00000932 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
-	2	-	not specified (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome (1)
-	1	-	Long QT syndrome 5 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.77		Loss of disorder (P = 0.0135)
MVP		0.98
MPC		0.50
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.87
Mutation Taster		=0/100	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: rs199473645; hg19: chr21-35821734;