rs794728466

Variant names:

• chr7-150947370-TCGCCCCGGGGC-T
• rs794728466
• NM_000238.4:c.3099_3109delGCCCCGGGGCG

Your query was ambiguous. Multiple possible variants found:

• chr7-150947370-TCGCCCCGGGGC-T
• chr7-150947370-TCGCCCCGGGGC-TCGCCCCGGGGCCGCCCCGGGGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.3099_3109delGCCCCGGGGCG​(p.Pro1034ArgfsTer81) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000388 in 1,546,550 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1033R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.60
• Publications: 1 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-150947370-TCGCCCCGGGGC-T is Pathogenic according to our data. Variant chr7-150947370-TCGCCCCGGGGC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 200697.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.3099_3109delGCCCCGGGGCG	p.Pro1034ArgfsTer81	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.3099_3109delGCCCCGGGGCG	p.Pro1034ArgfsTer81	frameshift_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151600 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394950 Hom.: 0 AF XY: 0.00000291 AC XY: 2 AN XY: 688198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31660

American (AMR) AF: 0.00 AC: 0 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 35882

South Asian (SAS) AF: 0.00 AC: 0 AN: 79154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5206

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078984

Other (OTH) AF: 0.00 AC: 0 AN: 57876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00921106), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151600 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74018

African (AFR) AF: 0.00 AC: 0 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 06, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Pro1034ArgfsX81 (P1034RfsX81; c.3099_3109del11) in the KCNH2 gene (NM_000238.2) Based on the evidence reviewed below, we classify it as likely disease causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The KCNH2 gene (also known as HERG) encodes potassium channel, voltage-gated, subfamily H, member 2 protein. It plays an essential role in the final repolarization of the ventricular action potential (Gianulis and Trudeau, 2011). This specific mutation in the KCNH2 gene has not been previously reported in the literature, according to GeneDx and to a search of PubMed and Google. However, it has been seen in one presumably unrelated individual tested for LQTS at GeneDx. We also have a SCICD patient with a similar frameshift mutation beginning at Pro1034 in KCNH2 (p.Pro1034fs; c.3095_3099dup4). This variant was interpreted on August 26, 2011, by genetic counselor Colleen Caleshu of the Stanford Center for Inherited Cardiovascular Disease. Familion classified this as a novel Class I variant. There was moderate segregation data from within this family: It co-segregated with LQTS in four affected individuals including the patient, her daughter, her brother and her father. Familion reported that they did not see the variant in 1300 presumably healthy individuals of mixed ancestry (published in Kapa et al. 2009). Taken together, these data strongly support this variant as the cause of LQTS in this patient and her family. Furthermore, this variant is of a type frequently seen to cause disease. c.3099_3109del11 creates a shift in reading frame starting at codon 1034, changing it from a proline to an arginine and creating a premature stop codon at position 81 of the new reading frame. This is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple frameshift mutations in the KCNH2 gene have been reported in individuals with LQTS (GeneDx references the Human Gene Mutation database: Stenson et al. 2003). Some of these frameshift mutations begin specifically at Pro1034 or nearbyresidues: p.Pro1034fs+18X (Kapplinger et al. 2009), p.Pro1034fx+21X (Kapplinger et al. 2009), p.Pro1034fx+83X (Kapplinger et al. 2009), p.Gly1031fs+86X (Napolitano et al. 2005), p.Gly1031fs+20X (Napolitano et al. 2005), p.Gly1031fs+24X (Splawski et al. 2000), p.Arg1032fs (Millat et al. 2006), p.Arg1033fs+22X (Napolitano et al. 2005), p.Arg1033fs+23X (Kapplinger et al. 2009), p.Arg1033fs+82X (Kapplinger et al. 2009) etc. This is not an exhaustive list. The variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The coverage at this site is ~34x in exomes and ~30x in genomes. -

Mar 01, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 126 amino acids are replaced with 80 different amino acids, and other loss-of-function variants have been reported downstream in HGMD -

Long QT syndrome Pathogenic:1

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 200697). This premature translational stop signal has been observed in individual(s) with clinical features of KCNH2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1034Argfs*81) in the KCNH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the KCNH2 protein. -

Cardiovascular phenotype Pathogenic:1

Nov 21, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3099_3109del11 pathogenic mutation, located in coding exon 13 of the KCNH2 gene, results from a deletion of 11 nucleotides at nucleotide positions 3099 to 3109, causing a translational frameshift with a predicted alternate stop codon (p.P1034Rfs*81). Similar C-terminal frameshift alterations have been reported in association with long QT syndrome (LQTS) in the literature, and functional studies have indicated that several of those alterations result in truncated proteins with deficient function (e.g., Sasano T et al. J. Mol. Cell. Cardiol. 2004;37:1205-11; Mihic A et al. PLoS ONE. 2011;6:e18273). This alteration is therefore expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728466; hg19: chr7-150644458;