7-150959590-TG-TGG

Variant names:

• chr7-150959590-T-TG
• rs761863251
• NM_000238.4:c.453dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.453dupC​(p.Thr152HisfsTer180) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,664 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: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 0.416

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 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 7-150959590-T-TG is Pathogenic according to our data. Variant chr7-150959590-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 503669.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.453dupC	p.Thr152HisfsTer180	frameshift_variant	Exon 3 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.453dupC	p.Thr152HisfsTer180	frameshift_variant	Exon 3 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.676dupC		non_coding_transcript_exon_variant	Exon 3 of 9	2
KCNH2	ENST00000684241.1	n.1286dupC		non_coding_transcript_exon_variant	Exon 1 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727146

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: 0.0000188

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Published in vitro functional studies demonstrate this variant alone failed to generate potassium current and when expressed with WT, it may enhance the WT channel function (Caballero et al., 2017); however, it is unclear how these studies may translate to a pathogenic role in vivo; Reported in ClinVar (ClinVar Variant ID# 503669; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 32383558, 32048431, 20851114, 28049825, 28166811, 26669661, 19716085, 15840476, 10973849, 16922724) -

Long QT syndrome Pathogenic:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr152Hisfs*180) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10973849, 20851114, 28049825). It has also been observed to segregate with disease in related individuals. This variant is also known as insC453–454* (P151fs/179) and c.453dup (p.Thr152fs). ClinVar contains an entry for this variant (Variation ID: 503669). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 17, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.453dupC pathogenic mutation, located in coding exon 3 of the KCNH2 gene, results from a duplication of C at nucleotide position 453, causing a translational frameshift with a predicted alternate stop codon (p.T152Hfs*180). This mutation has been detected in long QT syndrome cohorts, and has been reported to segregate with disease in a family (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Millat G et al. Clin. Chim. Acta, 2011 Jan;412:203-7; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6; Caballero R et al. Proc. Natl. Acad. Sci. U.S.A., 2017 01;114:E416-E425). 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. -

Long QT syndrome 2 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs761863251; hg19: chr7-150656678;