rs1402178514

Positions:

• chr21-34449498-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_000219.6(KCNE1):​c.137A>G​(p.Tyr46Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y46Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.88

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 19 pathogenic changes around while only 4 benign (83%) in NM_000219.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 21-34449498-T-C is Pathogenic according to our data. Variant chr21-34449498-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517181.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.137A>G	p.Tyr46Cys	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.137A>G	p.Tyr46Cys	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000101 AC: 1 AN: 988036 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 498238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000226

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 09, 2017

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 07, 2017

The p.Tyr46Cys variant in KCNE1 has been identified by our laboratory in the hom ozygous state in 1 individual with clinical features of Jervell and Lange-Nielse n syndrome (JLNS) and segregated in an affected sibling. This variant has been identified in 1/3494 Finnish chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org). Computational prediction tools and conse rvation analyses suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic for autosomal recessive JLNS. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

The p.Y46C variant (also known as c.137A>G), located in coding exon 1 of the KCNE1 gene, results from an A to G substitution at nucleotide position 137. The tyrosine at codon 46 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Roberts JD et al. Circulation, 2020 Feb;141:429-439). Limited functional studies have suggested this alteration may impact current amplitudes and pore conductance (Wang Y et al. J. Gen. Physiol., 2012 Dec;140:653-69). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	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	0.60	T
PROVEAN	Pathogenic	-8.3	D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.82
MutPred		0.31		Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);
MVP		0.95
MPC		0.48
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.95

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: rs1402178514; hg19: chr21-35821796;