rs199473018
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.2987A>T(p.Asn996Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N996S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2987A>T | p.Asn996Ile | missense_variant | 13/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2987A>T | p.Asn996Ile | missense_variant | 13/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1967A>T | p.Asn656Ile | missense_variant | 9/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3820A>T | non_coding_transcript_exon_variant | 11/13 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 36
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 20, 2023 | PS3, PS4_Supporting, PM2, PP2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 24, 2020 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies suggest the variant reduces channel current, prolongs action potentials, and decreases trafficking of channels to the cell's surface (Bellin M et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15851119, 15840476, 19841300, 22581653, 31737537, 22949429, 24213244) - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:15851119;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at