rs199473438
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000238.4(KCNH2):c.2758C>T(p.Arg920Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,529,092 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R920Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2758C>T | p.Arg920Trp | missense_variant | 12/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2758C>T | p.Arg920Trp | missense_variant | 12/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1738C>T | p.Arg580Trp | missense_variant | 8/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3591C>T | non_coding_transcript_exon_variant | 10/13 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152062Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 1AN: 125518Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 68518
GnomAD4 exome AF: 0.0000138 AC: 19AN: 1377030Hom.: 0 Cov.: 36 AF XY: 0.0000147 AC XY: 10AN XY: 678700
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152062Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2023 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 67433). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085). 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 920 of the KCNH2 protein (p.Arg920Trp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with tryptophan at codon 920 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has been identified in 1/125518 chromosomes 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | KCNH2: PM5, PM2:Supporting, PP2 - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2019 | The c.2758C>T (p.R920W) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2758, causing the arginine (R) at amino acid position 920 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces arginine with tryptophan at codon 920 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has been identified in 1/125518 chromosomes 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