rs189014161

chr7-150950336-G-Achr7-150950336-G-Cchr7-150950336-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):c.2230C>T(p.Arg744Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,218 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.20

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150950336-G-A is Pathogenic according to our data. Variant chr7-150950336-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150950336-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2230C>T	p.Arg744Ter	stop_gained	9/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2230C>T	p.Arg744Ter	stop_gained	9/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461218 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726942

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	May 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jun 25, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 29, 2014	- -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2023	This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg744*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). ClinVar contains an entry for this variant (Variation ID: 180383). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PVS1_Strong, PP1_Strong, PM2 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2021

Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease This variant is associated with the following publications: (PMID: 31018519, 33013630, 33304416, 31727422, 19716085, 25525159, 28775708, 26704558, 28363160, 11854117, 22338672, 19841298, 11802537) -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 25, 2018

The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT syndrome (Ko 2001, Moss 2002, Schwartz 2009, Kapplinger 2009, Crotti 2012), and 1 individual with LQTS and Charcot-Marie-Tooth disease, who also carried a dup of 17p11.2 (Losito 2009). This variant segregated with LQTS in 13 relatives from multiple families. This variant has also been reported in ClinVar (Variation ID 180383) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 744, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, absence from controls, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate (Richards 2015). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2020

The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in LQTS genetic testing cohorts, and has shown segregation with disease in two families (Ko YL et al. J. Formos. Med. Assoc., 2001 Nov;100:767-71; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.84
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs189014161; hg19: chr7-150647424;