rs794728403

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000238.4(KCNH2):c.3040C>T(p.Arg1014Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,561,932 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.96

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 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 7-150947440-G-A is Pathogenic according to our data. Variant chr7-150947440-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947440-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.3040C>T	p.Arg1014Ter	stop_gained	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.3040C>T	p.Arg1014Ter	stop_gained	13/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.2020C>T	p.Arg674Ter	stop_gained	9/11	1			Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3873C>T		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1409776

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

696168

show subpopulations

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:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 24, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	Reported in association with LQTS (Splawski et al., 2000; Gong et al., 2004; Tester et al., 2005); Reported in ClinVar as pathogenic (ClinVar Variant ID# 200518; Landrum et al., 2016); 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; Published mRNA functional studies demonstrate a damaging effect as this variant is shown to lead to a reduced level of mutant mRNA compared to that of the wild-type allele; therefore, the authors concluded that absence of R1014X protein product due to nonsense mediated mRNA decay causes loss of normal protein function (Gong et al., 2007); Additional functional studies demonstrate that this variant leads to a reduction of surface channel expression (Puckerin et al., 2016); This variant is associated with the following publications: (PMID: 15572053, 10973849, 19324319, 17576861, 26775140, 18675227, 15958262, 21419236, 15840476, 19716085, 14642687, 31737537, 30847666) -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change creates a premature translational stop signal (p.Arg1014*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with severe and mild long QT syndrome (PMID: 10973849, 14642687). ClinVar contains an entry for this variant (Variation ID: 200518). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2022	Variant summary: KCNH2 c.3040C>T (p.Arg1014X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 165078 control chromosomes. c.3040C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (example Splawski_2000, Lieve_2013, Westphal _2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes HERG channel dysfunction by defective trafficking of the mutant protein (Gong_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Long QT syndrome 2 (LQTS; MIM#613688). Gain of function is also a known mechanism associated with Short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other variants predicted to cause NMD have been reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with LQTS (ClinVar, PMID: 10973849, PMID: 30847666). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Congenital long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 19, 2023

The p.Arg1014X variant in KCNH2 has been reported in at least 3 individuals with long QT syndrome (LQTS; Splawski 2000 PMID: 10973849, Lieve 2013 PMID: 23631430, Westphal 2020 PMID: 32383558). It has also been reported by other clinical laboratories in ClinVar (Variation ID 200518) and was identified in 0.002% (1/41444) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1014, which is predicted to lead to a truncated or absent protein. This is corroborated by in vitro mRNA studies that show that this variant leads to a reduction of mRNA transcripts (Gong 2007 PMID: 17576861). Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in autosomal dominant long QT syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.72

MutationTaster

Benign

1.0

A;A;A

Vest4

0.81

GERP RS

4.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: -23

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