7-150947376-CG-CGG

Variant names:

• chr7-150947376-C-CG
• rs794728468
• NM_000238.4:c.3103dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000238.4(KCNH2):​c.3103dupC​(p.Arg1035ProfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R1035R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.67
• Publications: 4 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 12 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-C-CG is Pathogenic according to our data. Variant chr7-150947376-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 857501.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3103dupC	p.Arg1035ProfsTer84	frameshift_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3103dupC	p.Arg1035ProfsTer84	frameshift_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385836 Hom.: 0 Cov.: 35 AF XY: 0.00000293 AC XY: 2 AN XY: 683606

African (AFR) AF: 0.00 AC: 0 AN: 31326

American (AMR) AF: 0.00 AC: 0 AN: 35236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24590

East Asian (EAS) AF: 0.00 AC: 0 AN: 33126

South Asian (SAS) AF: 0.00 AC: 0 AN: 79008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1075150

Other (OTH) AF: 0.00 AC: 0 AN: 57250

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Pathogenic:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1035Profs*84) in the KCNH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the KCNH2 protein. This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the KCNH2 protein in which other variant(s) (p.Glu1119*) have been determined to be pathogenic (PMID: 27920829). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 857501). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs794728468; hg19: chr7-150644464;