rs794728469

Positions:

• chr7-150947372-GC-G
• chr7-150947372-GC-GCC
• chr7-150947372-GC-GCCC
• chr7-150947372-GC-GCCCC
• chr7-150947372-GC-GCCCCC

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.3107delG​(p.Gly1036fs) 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 (★★). 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.40

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 7-150947372-GC-G is Pathogenic according to our data. Variant chr7-150947372-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 200801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947372-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3107delG	p.Gly1036fs	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.3107delG	p.Gly1036fs	frameshift_variant	13/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2087delG	p.Gly696fs	frameshift_variant	9/11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3940delG		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395090 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 688188

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 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; Reported in individuals with suspicion of long QT syndrome or affected with sudden arrhythmic death syndrome (Lieve et al., 2013; Lahrouchi et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23631430, 28449774) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 200801). This premature translational stop signal has been observed in individuals with suspicion of long QT syndrome or sudden arrhythmic death syndrome (PMID: 23631430, 28449774). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly1036Alafs*21) 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). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2018

The c.3107delG pathogenic mutation, located in coding exon 13 of the KCNH2 gene, results from a deletion of one nucleotide at position 3107, causing a translational frameshift with a predicted alternate stop codon (p.G1036Afs*21). This alteration has been reported in a long QT syndrome (LQTS) cohort and a sudden death cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Lahrouchi N et al. J. Am. Coll. Cardiol., 2017 May;69:2134-2145). 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

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: rs794728469; hg19: chr7-150644460;