rs794728466

chr7-150947370-TCGCCCCGGGGC-Tchr7-150947370-TCGCCCCGGGGC-TCGCCCCGGGGCCGCCCCGGGGC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000238.4(KCNH2):c.3099_3109del(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. 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

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 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 [Likely_pathogenic]. Clinvar id is 200697.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.3099_3109del	p.Pro1034ArgfsTer81	frameshift_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3099_3109del	p.Pro1034ArgfsTer81	frameshift_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2079_2089del	p.Pro694ArgfsTer81	frameshift_variant	9/11	1
KCNH2	ENST00000684241.1	n.3932_3942del		non_coding_transcript_exon_variant	11/13

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

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: 0.00000371

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

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

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 06, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

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. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of KCNH2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 200697). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2018

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728466; hg19: chr7-150644458;