Variant chr7-150974776-TGCGCGGCA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000238.4(KCNH2):c.234_241delTGCCGCGC(p.Ala79fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.70

Variant links:

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 links:

KCNH2 (HGNC:):

KCNH2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 7-150974776-TGCGCGGCA-T is Pathogenic according to our data. Variant chr7-150974776-TGCGCGGCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 264104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974776-TGCGCGGCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.234_241delTGCCGCGC	p.Ala79fs	frameshift_variant	2/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.234_241delTGCCGCGC	p.Ala79fs	frameshift_variant	2/15	1	NM_000238.4	ENSP00000262186.5		Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.457_464delTGCCGCGC		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453902

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

722798

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 28, 2022

Heterozygous mutation c.234_241del (p.Ala79AspfsTer63) in KCNH2 gene was found in male proband (13 y.o., Caucasian) with Long QT syndrome. This variant is absent in Genome Aggregation Database (gnomAD) (date of access 2022-11-22). Functional analysis shows this mutation leads to a loss of hERG potassium channel function (PMID: 19668779). The variant has been reported in several articles (PMID: 36102233, 23098067, 19716085, 19668779). ClinVar contains entry on this variant (Variation ID: 264104). In accordance with ACMG(2015) criteria this variant is classified as Pathogenic with following criteria selected: PVS1, PS3, PS4_moderate, PM2. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 13, 2020

PVS1, PS3, PS4_Moderate, PM2 -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2015

The c.234_241delTGCCGCGC pathogenic mutation, located in coding exon 2 of the KCNH2 gene, results from a deletion of 8 nucleotides between positions 234 and 241, causing a translational frameshift with a predicted alternate stop codon. This mutation was detected in a proband with sports-induced syncope in childhood, atypical ECG findings, and family history which included seizures, dizziness, and abnormal ECG findings consistent with LQTS2 (Keller DI et al. Can J Cardiol 2009;25(8):455-62). In another study, this mutation was detected in two of 2500 individuals referred for LQTS-related genetic testing (Kapplinger JD et al. Heart Rhythm 2009;6(9):1297-303). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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