rs199472834
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000238.4(KCNH2):c.94G>A(p.Ala32Thr) variant causes a missense change involving the alteration of a 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32V) has been classified as Pathogenic.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.94G>A | p.Ala32Thr | missense_variant | 2/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.94G>A | p.Ala32Thr | missense_variant | 2/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.317G>A | non_coding_transcript_exon_variant | 2/9 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1454392Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 723232
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 32 of the KCNH2 protein (p.Ala32Thr). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810, 32475984). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67549). This missense change has been observed in individual(s) with long QT syndrome or its clinical features (PMID: 19716085; Invitae). This variant is not present in population databases (gnomAD no frequency). - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 06, 2020 | This missense variant replaces alanine with threonine at codon 32 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual referred for the long QT syndrome clinical genetic test (PMID: 19716085). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
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:19716085). 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