rs794728468

Positions:

• chr7-150947376-CG-C
• chr7-150947376-CG-CGG

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.3103delC​(p.Arg1035fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.67

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 (HGNC:):

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 7-150947376-CG-C is Pathogenic according to our data. Variant chr7-150947376-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 200701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947376-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3103delC	p.Arg1035fs	frameshift_variant	13/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3103delC	p.Arg1035fs	frameshift_variant	13/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2083delC	p.Arg695fs	frameshift_variant	9/11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3936delC		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385836 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 683606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	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: 16414944, 15840476, 19862833, 32695588, 36861347, 21063070) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change creates a premature translational stop signal (p.Arg1035Glyfs*22) 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 long QT syndrome (PMID: 15840476, 21063070). This variant is also known as P1034fs/21*. ClinVar contains an entry for this variant (Variation ID: 200701). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs794728468; hg19: chr7-150644464;