rs730880116

Positions:

• chr7-150958290-C-A
• chr7-150958290-C-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.685G>T​(p.Glu229Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E229E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.718

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 7-150958290-C-A is Pathogenic according to our data. Variant chr7-150958290-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 180379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150958290-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.685G>T	p.Glu229Ter	stop_gained	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.685G>T	p.Glu229Ter	stop_gained	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.908G>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1518G>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1314242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 648660

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 07, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2016

The E229X pathogenic variant in the KCNH2 gene has been previously reported in multiple individuals in association with LQTS (Tester et al., 2005; Tester et al., 2006; Berge et al., 2008; Goldenberg et al., 2011). This variant was also observed in one affected individual from a family referred for LQTS genetic testing at GeneDx, and was found to segregate with a prolonged QT interval in a second family member. E229X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, multiple other nonsense variants in the KCNH2 gene have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Finally, while data from control individuals was not sufficient to assess whether E229X may be a common benign variant in the general population, Tester et al. (2005) previously reported E229X to be absent from over 1,400 reference alleles.In summary, E229X in the KCNH2 gene is interpreted as a pathogenic variant. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2023

This sequence change creates a premature translational stop signal (p.Glu229*) 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 undergoing testing for long QT syndrome (PMID: 15840476, 16818214, 18752142, 19716085). ClinVar contains an entry for this variant (Variation ID: 180379). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2018

The p.E229* pathogenic mutation (also known as c.685G>T), located in coding exon 4 of the KCNH2 gene, results from a G to T substitution at nucleotide position 685. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation has been reported in multiple unrelated probands in several publications on long QT syndrome clinical genetic testing; however, clinical details are limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8; Tester DJ et al. Heart Rhythm, 2006 Jul;3:815-21). 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	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.74
GERP RS		2.6

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: rs730880116; hg19: chr7-150655378;