rs199473434

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3PP5BS2_Supporting

The NM_000238.4(KCNH2):c.2684C>T(p.Thr895Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000301 in 1,230,738 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T895T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7O:1

Conservation

PhyloP100: 3.77

Variant links:

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a mutagenesis_site Abolishes phosphorylation; when associated with A-283; A-890 and A-1137. (size 0) in uniprot entity KCNH2_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

PP5

Variant 7-150948452-G-A is Pathogenic according to our data. Variant chr7-150948452-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67426.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=7}.

BS2

High AC in GnomAd4 at 7 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2684C>T	p.Thr895Met	missense_variant	11/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2684C>T	p.Thr895Met	missense_variant	11/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1664C>T	p.Thr555Met	missense_variant	7/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3517C>T		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

130820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00106

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000158

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243318

Hom.:

AF XY:

0.00000755

AC XY:

AN XY:

132456

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1099880

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

550626

show subpopulations

Gnomad4 AFR exome

AF:

0.0000823

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000860

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.0000486

GnomAD4 genome

AF:

0.0000535

AC:

AN:

130858

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

62152

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00106

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000158

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.2684C>T;p.(Thr895Met) missense change has been observed in affected individual(s)(PMID: 26129877; 18596570; 23304551; 21215473; 20674198) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26129877; 18596570) - PS3_supporting. The variant is present at low allele frequencies population databases (rs199473434– gnomAD 0.0005351%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces threonine with methionine at codon 895 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An electrophysiological study in cell culture has shown that this variant may affect the deactivation time course of the potassium channels (PMID: 26129877). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with atrial fibrillation, as well as in the proband's father and son affected with paroxysmal palpitations (PMID: 26129877). This variant has been reported in an infant affected with sudden death syndrome (PMID: 18596570). This variant has also been identified in 6/273882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 895 of the KCNH2 protein (p.Thr895Met). This variant is present in population databases (rs199473434, gnomAD 0.01%). This missense change has been observed in individual(s) with atrial fibrillation and in two relatives with paroxysmal palpitations (PMID: 18596570, 26129877). ClinVar contains an entry for this variant (Variation ID: 67426). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18596570, 26129877). 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 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 17, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2020

Identified in a Japanese patient with sudden infant death syndrome who also harbored a variant in the SCN5A gene (Otagiri et al., 2008); Identified in a Japanese man, his father, and his son, all of whom were affected with persistent or paroxysmal palpitations; the proband's ECG showed a normal QTc interval (Hayashi et al., 2015); Published functional studies suggested a gain-of-function effect (Otagiri et al., 2008; Hayashi et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31043699, 18596570, 26129877, 22581653, 26332594, 22995991) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2022

The c.2684C>T (p.T895M) alteration is located in exon 11 (coding exon 11) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2684, causing the threonine (T) at amino acid position 895 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2023

This missense variant replaces threonine with methionine at codon 895 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro functional studies have shown that this variant may affect the amplitude of current and causes a delay in deactivation of the potassium channels (PMID: 18596570, 26129877). This variant has been reported in an individual affected with atrial fibrillation, as well as in the proband's father and son affected with paroxysmal palpitations (PMID: 26129877). This variant has also been reported in an infant affected with sudden death syndrome (PMID: 18596570), and in two individuals suspected of having epilepsy (PMID: 31696929). This variant has also been identified in 6/273882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

SUDDEN INFANT DEATH 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 Sudden infant death syndrome in the following publications (PMID:18596570). 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

Benign

0.15

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.7

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.5

N;N

REVEL

Pathogenic

0.76

Sift

Benign

0.17

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.98

D;D

Vest4

0.68

MVP

0.98

MPC

0.47

ClinPred

0.87

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.082

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over