rs199473362

Positions:

• chr21-34449343-G-C
• chr21-34449343-G-T
• chr21-34449343-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000399286.3(KCNE1):​c.292C>G​(p.Arg98Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R98L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 ENST00000399286.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 2.58

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 helix (size 13) in uniprot entity KCNE1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in ENST00000399286.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449343-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132676.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=2, not_provided=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.292C>G	p.Arg98Gly	missense_variant	4/4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.292C>G	p.Arg98Gly	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 22, 2015

The p.Arg98Gly variant in KCNE1 has not been previously reported in individuals with hearing loss, Jervell and Lange-Nielsen syndrome, or long QT syndrome. This variant was absent from large population studies. A different variant at the sa me amino acid position (p.Arg98Trp) has been associated with long QT syndrome su ggesting that variants at this position may not be tolerated. However, this asso ciation requires additional data to assume pathogenicity for the p.Arg98Trp vari ant, and the impact of the two amino acid changes at the same position may be di fferent. Computational prediction tools and conservation analysis for the p.Arg9 8Gly variant do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Arg98Gly variant is uncertain . -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 14, 2019

This sequence change replaces arginine with glycine at codon 98 of the KCNE1 protein (p.Arg98Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228763). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Long QT syndrome 5 Other:1

not provided, no classification provided

in vitro

Roden Lab, Vanderbilt University Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D;D;D;D;D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	.;.;T;.;.;.;.;.
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;M
MutationTaster	Benign	0.59	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;.;.;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D
Polyphen		0.97	D;D;D;D;D;D;D;D
Vest4		0.41
MutPred		0.48		Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);
MVP		0.93
MPC		0.48
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.21
gMVP		0.73

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: rs199473362; hg19: chr21-35821641;