rs541259035
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000238.4(KCNH2):c.3163C>T(p.Arg1055Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,600,770 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. R1055Q) has been classified as Benign.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.3163C>T | p.Arg1055Trp | missense_variant | 14/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.3163C>T | p.Arg1055Trp | missense_variant | 14/15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.2143C>T | p.Arg715Trp | missense_variant | 10/11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3996C>T | non_coding_transcript_exon_variant | 12/13 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151802Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000287 AC: 7AN: 243848Hom.: 0 AF XY: 0.0000379 AC XY: 5AN XY: 131860
GnomAD4 exome AF: 0.0000145 AC: 21AN: 1448850Hom.: 0 Cov.: 33 AF XY: 0.0000181 AC XY: 13AN XY: 718580
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151920Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74238
ClinVar
Submissions by phenotype
Long QT syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1055 of the KCNH2 protein (p.Arg1055Trp). This variant is present in population databases (rs541259035, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 405340). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2023 | The p.R1055W variant (also known as c.3163C>T), located in coding exon 14 of the KCNH2 gene, results from a C to T substitution at nucleotide position 3163. The arginine at codon 1055 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in an acquired long QT syndrome cohort (Gray B et al. Circ Genom Precis Med, 2022 Feb;15:e003391). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at