7-150947785-TC-TCC

Variant names:

• chr7-150947785-T-TC
• rs794728458
• NM_000238.4:c.2785dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2785dupG​(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:5
• Conservation: PhyloP100: 1.34
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 200678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2785dupG	p.Glu929GlyfsTer11	frameshift_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2785dupG	p.Glu929GlyfsTer11	frameshift_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5

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

African (AFR) AF: 0.00 AC: 0 AN: 31428

American (AMR) AF: 0.00 AC: 0 AN: 35538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25064

East Asian (EAS) AF: 0.00 AC: 0 AN: 35626

South Asian (SAS) AF: 0.00 AC: 0 AN: 78984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076876

Other (OTH) AF: 0.00 AC: 0 AN: 57590

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:2

Jun 06, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 08, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1;PM2;PS4_supp;PP5 -

not provided Pathogenic:1

Mar 31, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 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). Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Mar 05, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728458; hg19: chr7-150644873;