rs199473506

Positions:

• chr7-150952777-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.1205A>G​(p.His402Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.87

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-150952777-T-C is Pathogenic according to our data. Variant chr7-150952777-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67166.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1205A>G	p.His402Arg	missense_variant	6/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1205A>G	p.His402Arg	missense_variant	6/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2022

Published functional studies demonstrate a damaging effect; specifically in vitro analyses demonstrated reduced membrane channel expression and significantly altered gating properties of the expressed channel that resulted in altered physiological phenotypes associated with H402R-hERG relative to WT-hERG (PMID: 28280240); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23631430, 19716085, 21185501, 19136169, 22581653, 26669661, 28280240) -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 21, 2017

This variant identified in the KCNH2 gene is located in the cytoplasmic N-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. This sequence change replaces histidine with arginine at codon 402 of the KCNH2 protein (p.His402Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (rs199473506, ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 19136169, Invitae), as well as in an individual referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67166). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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:19136169;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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.6	D;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.96	D;P;.
Vest4		0.95
MutPred		0.85		.;Gain of solvent accessibility (P = 0.0021);.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.97

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: rs199473506; hg19: chr7-150649865; COSMIC: COSV100058768;