7-150947785-TC-TCC

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.2785_2786insG(p.Glu929GlyfsTer11) 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.34

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 7-150947785-T-TC is Pathogenic according to our data. Variant chr7-150947785-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2785_2786insG	p.Glu929GlyfsTer11	frameshift_variant	12/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2785_2786insG	p.Glu929GlyfsTer11	frameshift_variant	12/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1765_1766insG	p.Glu589GlyfsTer11	frameshift_variant	8/11	1
KCNH2	ENST00000684241.1	n.3618_3619insG		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382688 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 681840

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/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2022

Reported in association with LQTS in the published literature (Tester et al., 2005; Perkins et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 15840476, 29555771) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). This variant has been observed in an individual referred for testing for long QT syndrome (LQTS) (PMID: 15840476, 29555771). This variant is also described as ins G 2785-2786 (G928fs/10*) in the literature. ClinVar contains an entry for this variant (Variation ID: 200678). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Glu929Glyfs*11) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The c.2785dupG pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a duplication of G at nucleotide position 2785, causing a translational frameshift with a predicted alternate stop codon (p.E929Gfs*11). This variant (also referred to as insG 2785–2786, G928fs/10*) has been detected in a cohort referred for long QT syndrome genetic testing (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17). 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

Mar 05, 2020

This variant inserts 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. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in an individual referred for testing for long QT syndrome (LQTS) (PMID:15840476). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs794728458; hg19: chr7-150644873;