Variant 7-150947795-GC-GCC details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000262186.10(KCNH2):c.2775_2776insG(p.Pro926AlafsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,532,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G925?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KCNH2
ENST00000262186.10 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.37

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 7-150947795-G-GC is Pathogenic according to our data. Variant chr7-150947795-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 200672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2775_2776insG	p.Pro926AlafsTer14	frameshift_variant	12/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2775_2776insG	p.Pro926AlafsTer14	frameshift_variant	12/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1755_1756insG	p.Pro586AlafsTer14	frameshift_variant	8/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3608_3609insG		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000783

AC:

AN:

127658

Hom.:

AF XY:

0.00

AC XY:

AN XY:

69796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.25e-7

AC:

AN:

1380062

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680378

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:

0.0000274

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000869

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2022	Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22988594, 21215473, 21419236, 24065925, 23304551, 28363160, 10973849, 20181576, 22956155, 30369311, 26669661, 29739726, 16922724, 32383558, 34319147, 34127479, 27000522) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2023	The KCNH2 c.2775dup; p.Pro926Alafs*14 variant (rs794728455) is reported in the literature in multiple individuals in the heterozygous state affected with Long QT syndrome (Choi 2021, Nof 2010, Westphal 2020, Zarraga 2011). This variant is reported in ClinVar (Variation ID: 200672) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. In vitro/In vivo functional analyses demonstrate reduced cellular currents (Nof 2010, Zarraga 2011). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Choi SH et al. Rare Coding Variants Associated with Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis. Circ Genom Precis Med. 2021. PMID: 34319147. Nof E et al. A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death. Circ Cardiovasc Genet. 2010. PMID: 20181576. Westphal DS. Reclassification of genetic variants in children with long QT syndrome. Mol Genet Genomic Med. 2020. PMID: 32383558. Zarraga IG et al. Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome. Heart Rhythm. 2011. PMID: 21419236. -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Pro926Alafs*14) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10973849, 20181576, 21419236). ClinVar contains an entry for this variant (Variation ID: 200672). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant causes a duplication of 1 nucleotide in exon 12 of the KCNH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes decreased expression of KCNH2 resulting in a reduction in channel current density in HEK293 cells (PMID: 20181576, 21419236). This variant has been reported in at least eight unrelated individuals affected with long QT syndrome (PMID: 10973849, 21419236, 20181576, 26669661, 30369311, 32383558). It has been shown that this variant segregates with disease in multiple individuals from two of these families (PMID: 20181576, 21419236). This variant has also been reported in an individual affected with sudden cardiac death (PMID: 27000522). This variant has been identified in 1/127658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Long QT syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Long QT syndrome 1/2, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

The c.2775dupG pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a duplication of G at nucleotide position 2775, causing a translational frameshift with a predicted alternate stop codon (p.P926Afs*14). This alteration was identified in several members of a large long QT syndrome type 2 (LQTS2) kindred with complete segregation in affected individuals (Zarraga IG et al. Heart Rhythm. 2011;8(8):1200-6). Functional analysis from this group demonstrated this duplication results in the absence of protein from this allele. This alteration was also reported in affected relatives in a family with a history of sudden cardiac death and prolonged QTc intervals (Cann F et al, 2017 01;91:22-29). Additionally, this alteration was reported as heterozygous in a child and mother both affected with LQTS2. The mother had a history of two other pregnancies with this alteration in addition to a paternally inherited KCNH2 alteration; these babies did not survive, and functional studies indicated that the effect of both alterations together is more severe than either alone (Nof E et al. Circ Cardiovasc Genet. 2010;3(2):199-206). 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. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 24, 2023

This variant causes a duplication of 1 nucleotide in exon 12 of the KCNH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes decreased expression of KCNH2 resulting in a reduction in channel current density in HEK293 cells (PMID: 20181576, 21419236). This variant has been reported in at least eight unrelated individuals affected with long QT syndrome (PMID: 10973849, 21419236, 20181576, 26669661, 30369311, 32383558). It has been shown that this variant segregates with disease in multiple individuals from two of these families (PMID: 20181576, 21419236). This variant has also been reported in an individual affected with sudden cardiac death (PMID: 27000522). This variant has been identified in 1/127658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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