rs786204101

Positions:

• chr7-150947670-C-CG

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.2900_2901insC​(p.Pro968AlafsTer151) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P967P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.509

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 7-150947670-C-CG is Pathogenic according to our data. Variant chr7-150947670-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 188144.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	c.2900_2901insC	p.Pro968AlafsTer151	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	c.2900_2901insC	p.Pro968AlafsTer151	frameshift_variant	12/15	1	NM_000238.4	ENSP00000262186	P1
KCNH2	ENST00000330883.9	c.1880_1881insC	p.Pro628AlafsTer151	frameshift_variant	8/11	1		ENSP00000328531
KCNH2	ENST00000684241.1	n.3733_3734insC		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

deCODE genetics, Amgen

Jul 21, 2023

The variant NM_000238.4:c.2900dup (chr7:150947670) in KCNH2 was detected in 8 heterozygotes out of 58K WGS Icelanders (MAF= 0,007%). Following imputation in a set of 166K Icelanders (20 imputed heterozygotes) we observed an association with an elongation of the qt interval on ECG using measurements from 80068 individuals (Effect (SD)= 1.18, P= 3.38e-03). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2016

The c.2900dupC pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS (Berge et al., 2008; Seethala et al., 2015). The c.2900dupC varaint causes a shift in reading frame starting at codon Proline 968, changing it to an Alanine, and creating a premature stop codon at position 151 of the new reading frame, denoted p.Pro968AlafsX151. This pathogenic variant is expected to result in an abnormal protein product. Other frameshift variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.2900dupC variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 9.0). -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 25, 2015

This sequence change has been reported in one individual affected with long QT syndrome (PMID: 18752142) and is not present in population databases. This sequence change duplicates a C nucleotide in exon 12 of the KCNH2 mRNA (c.2900dupC), causing a frameshift at codon 968. This creates a premature translational stop signal (p.Pro968Alafs*151) and is expected to result in an absent or truncated protein product. Truncating sequence changes in KCNH2 are known to be pathogenic (PMID: 10973849, 17576861). In summary, this is a truncating sequence change  which is not reported in population databases, and has been observed in in one individual affected with long QT. For these reasons, this sequence change has been classified as Pathogenic -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs786204101; hg19: chr7-150644758;