rs121912508

Positions:

• chr7-150951649-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1744C>T​(p.Arg582Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R582L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951648-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-150951649-G-A is Pathogenic according to our data. Variant chr7-150951649-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951649-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1744C>T	p.Arg582Cys	missense_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1744C>T	p.Arg582Cys	missense_variant	7/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	Reported as a potential founder mutation from the Netherlands (Hofman et al., 2011); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 14428; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in impaired protein trafficking and channel inactivation (Fougere et al., 2011); This variant is associated with the following publications: (PMID: 10220144, 21376840, 15840476, 19716085, 21350584, 17088455, 9973011, 19038855, 12566525, 18441445, 17293393, 22949429, 32686758) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Congenital long QT syndrome Pathogenic:1 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:10220144;PMID:11222472;PMID:12566525;PMID:12877697;PMID:15840476;PMID:19716085;PMID:19841300;PMID:21376840). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2022	The p.Arg582Cys (c.1744C>T) variant in KCNH2 has been reported in 17 individuals with Long QT Syndrome (Wilde 1999 PMID: 9973011, Tester 2005 PMID: 15840476, Tan 2006 PMID: 17088455, Nemec 2003 PMID: 12877697, Nagaoka 2008 PMID: 18441445, Lupoglazoff 2001 PMID: 11222472, Kapplinger 2009 PMID: 19716085, Jongbloed 1999 PMID: 10220144, Hofman 2011 PMID: 21350584). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 29467). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein trafficking and function (Tseng 2007 PMID: 17293393, Fougere 2011 PMID: 21376840); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Long QT Syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting. -

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 582 of the KCNH2 protein (p.Arg582Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LQTS plus a seizure phenotype and Long QT syndrome (LQTS) (PMID: 10220144, 12566525, 18441445, 19038855, 21350584, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14428). 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: 21376840). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.1744C>T (p.R582C) alteration is located in exon 7 (coding exon 7) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in individuals and families reported to have long QT syndrome (LQTS), or from LQTS cohorts, and has been described as a possible founder mutation in the Netherlands (Jongbloed, 1999; Nagaoka, 2008; Johnson, 2009; Hofman, 2011). This amino acid position is not well conserved in available vertebrate species. In in vitro studies, this variant has been reported to result in abnormal protein trafficking and channel function (Fougere, 2011; Perry, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;D
Eigen	Benign	0.16
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.70
MutPred		0.92		.;Loss of disorder (P = 0.0259);.;
MVP		1.0
MPC		2.4
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.34
gMVP		0.84

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: rs121912508; hg19: chr7-150648737; COSMIC: COSV51220645;