rs199473434

chr7-150948452-G-Achr7-150948452-G-Cchr7-150948452-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP3 PP5 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T895K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 O:1
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000238.4
• 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: {Uncertain_significance=7, not_provided=1, Likely_pathogenic=2}.
• BS2: High AC in GnomAd at 7 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2684C>T	p.Thr895Met	missense_variant	11/15	ENST00000262186.10

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000535 AC: 7 AN: 130820 Hom.: 0 Cov.: 30

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: 5 AN: 243318 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132456

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: 30 AN: 1099880 Hom.: 0 Cov.: 35 AF XY: 0.0000291 AC XY: 16 AN XY: 550626

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: 7 AN: 130858 Hom.: 0 Cov.: 30 AF XY: 0.0000161 AC XY: 1 AN XY: 62152

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: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1 Uncertain: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	Mendelics	May 28, 2019	- -
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. -

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	Invitae	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
CardioboostArm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
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	D
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

Other links and lift over

dbSNP: rs199473434; hg19: chr7-150645540; COSMIC: COSV51253220; COSMIC: COSV51253220;