rs864622403
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000238.4(KCNH2):c.1582C>T(p.Arg528Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,228 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. R528P) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1582C>T | p.Arg528Trp | missense_variant | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1582C>T | p.Arg528Trp | missense_variant | 7/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 34
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1435916Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 710040
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2022 | Reported in association with LQTS in published literature (Marschall et al., 2019), however, patient-specific information not provided; Not observed at significant frequency in large population cohorts (gnomAD); 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: 16166152, 31737537) - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 05, 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16166152). 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. ClinVar contains an entry for this variant (Variation ID: 220162). This missense change has been observed in individual(s) with long QT syndrome (PMID: 31737537; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 528 of the KCNH2 protein (p.Arg528Trp). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2018 | The p.R528W variant (also known as c.1582C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1582. The arginine at codon 528 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been previously reported in a cohort of individuals referred for long QT syndrome genetic testing, but clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). In vitro functional studies in Xenopus oocytes has suggested that this variant may impact protein function; however, the physiological relevance of that impact is unclear (Subbiah RN et al. J. Physiol. (Lond.). 2005;569:367-79). This amino acid position is highly 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. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 30, 2018 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain S4 of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant decreases the rate of deactivation and and increase the rate of activation of the potassium channel (PMID: 16166152). However, clinical significance of this finding is not clear. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at