7-150959590-TG-TGG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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
Consequence
NM_000238.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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: 2AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727146
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at