rs79654911

chr21-34449435-C-Tchr21-34449435-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000219.6(KCNE1):c.200G>A(p.Arg67His) variant causes a missense change. The variant allele was found at a frequency of 0.0000903 in 1,538,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 5.01

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000219.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449436-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132660.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4, not_provided=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.200G>A	p.Arg67His	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.200G>A	p.Arg67His	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 24 AN: 134000 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000233

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000566

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251394 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135902

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000819 AC: 115 AN: 1404590 Hom.: 0 Cov.: 26 AF XY: 0.0000870 AC XY: 61 AN XY: 701296

Gnomad4 AFR exome AF: 0.0000923

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.0000512

GnomAD4 genome AF: 0.000179 AC: 24 AN: 134000 Hom.: 0 Cov.: 17 AF XY: 0.000201 AC XY: 13 AN XY: 64662

Gnomad4 AFR AF: 0.000333

Gnomad4 AMR AF: 0.0000755

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000233

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000566

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2023	Identified in patients with sudden unexplained death (SUD) and unexplained intrauterine fetal death (IUFD) (Skinner et al., 2011; Marcondes et al., 2018; Liebrechts-Akkerman et al., 2020; Muin et al., 2021); Identified in at least one patient with LVNC in published literature (Li et al., 2018; Li et al., 2019); Published functional studies suggest that R67H may impact channel function; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 21576493); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26410412, 22581653, 25637381, 24710009, 19716085, 34426522, 31679457, 32058015, 31397097, 30847666, 23631430, 31941373, 33281875, 21070882, 33762593, 30461122, 32145446, 30371277, 21576493, 29672598) -

Long QT syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 67 of the KCNE1 protein (p.Arg67His). This variant is present in population databases (rs79654911, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of KCNE1-related conditions (PMID: 19716085, 21070882, 24710009, 31941373). ClinVar contains an entry for this variant (Variation ID: 132661). 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: 21576493). This variant disrupts the p.Arg67 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been observed in individuals with KCNE1-related conditions (PMID: 31941373), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 06, 2014

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNE1 p.Arg67His The variant was re-reviewed on November 6, 2014. There was no new data. Based on the data reviewed below we consider this a variant of uncertain significance, likely disease-causing. We hesitate to classify this variant as likely disease-causing given the case data is mostly unpublished cases (some without clinical data) and that it is present in controls, albeit in a small number of individuals. The variant was reviewed at an SCICD team meeting and the team agreed upon this classification. The variant has been seen in at least 8 unrelated cases, (most without good clinical data to determine LQTS) and one case of sudden cardiac arrest, with possible failure to segregate in one case. The p.Arg67His variant is a conservative amino acid substitution of one positively charged residue for another. This variant is located in exon 3 of the KCNE1 gene in the C-terminal region. This variant has been reported in one individual referred for LQTS testing (Kapplinger et al., 2009). This was a report of 2500 individuals tested for LQTS through Familion laboratories. No individual data was given for this individual. Another variant at the same codon Arg67Cys was also reported in one individual in this cohort. Of the 902 individuals who had a rare variant in one of the tested genes, 24 of the them had a variant in KCNE1 gene. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Per an email from Familion, they have seen it in 5 probands referred for LQTS testing (presumably including the case reported by Kapplinger in 2009). All probands were caucasian and four of the QT measurements were 488-556ms, 520m, 481ms and 474ms. They report a positive family history was seen in at least two probands, but they do not have segregation data. GeneDx reports that Arg67His and several other novel changes, Arg67Leu, Arg67Ser and Arg67Gly have been observed in several unrelated individuals referred for LQTS testing at GeneDx. GeneDx clarified that they have seen the R67H variant in at least three individuals tested for LQTS, with no segregation data. This variant was also reported in a case of sudden unexplained death in a 17 year old female. Testing was done post-mortem. She was found dead in bed. A few months earlier she had experienced a nocturnal seizure with enuresis. Her other medical history was unremarkable. Her mother, whose nephew had died of cot death in infancy, had maximal QTc of 470 msec. However, the mother had no symptoms and did not carry the R67H variant. The father declined testing. The authors indicate that this variant was also seen in a girl with LQTS in Norway and that her mother had a normal QT interval and was also a gene carrier. No reference was given and I could not find another case report of this variant (Skinner et al., 2011 on behalf of the Cardiac Inherited Disease Group New Zealand). There are two ClinVar entries, both from Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust. One notes an assertion of pathogenic (SCV000153792). Neither provide any internal data. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. Mutation Taster predicts this variant to be disease-causing. The arginine at codon 67 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg67Cys; Arg67Ser; Arg67Gly) and nearby co -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

The c.200G>A (p.R67H) alteration is located in exon 3 (coding exon 1) of the KCNE1 gene. This alteration results from a G to A substitution at nucleotide position 200, causing the arginine (R) at amino acid position 67 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.88
MVP		0.98
MPC		0.48
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.56
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs79654911; hg19: chr21-35821733;