chr7-150947804-GC-G

Variant names:

• chr7-150947804-GC-G
• rs1554424403
• NM_000238.4:c.2766delG

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.2766delG​(p.Pro923ArgfsTer51) 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)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.481
• Publications: 0 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 7-150947804-GC-G is Pathogenic according to our data. Variant chr7-150947804-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.2766delG	p.Pro923ArgfsTer51	frameshift	Exon 12 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2478delG	p.Pro827ArgfsTer51	frameshift	Exon 10 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1746delG	p.Pro583ArgfsTer51	frameshift	Exon 8 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2766delG	p.Pro923ArgfsTer51	frameshift	Exon 12 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1746delG	p.Pro583ArgfsTer51	frameshift	Exon 8 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2700delG	p.Pro901ArgfsTer51	frameshift	Exon 12 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:2

Nov 27, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2766delG pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a deletion of one nucleotide at nucleotide position 2766, causing a translational frameshift with a predicted alternate stop codon (p.P923Rfs*51). This alteration has been reported in one individual from a long QT syndrome testing cohort (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.

Jul 10, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The KCNH2 c.2766delG (p.Pro923Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. c.2959_2960delCT (p.Leu987fs) and c.3107dupG (p.Asp1037fs). This variant is absent in 11608 control chromosomes (ExAC and publication controls). A publication, Tester_2005, cites the variant in an affected individual for LQTS. A functional study, Hsueh_2008, indicates the variant to cause reduced current amplitude and faster inactivation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Likely Pathogenic."

not provided Pathogenic:1

Oct 15, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient referred for LQTS genetic testing; however, additional clinical information was not provided (Tester et al., 2005); Not observed in large population cohorts (Lek et al., 2016); 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: 18593567, 15840476, 19841300)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48
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: rs1554424403; hg19: chr7-150644892;