7-150951643-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.1750G>A(p.Gly584Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,876 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 Likely pathogenic (★★).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1750G>A | p.Gly584Ser | missense_variant | Exon 7 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461876Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727240
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:4
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not provided Pathogenic:3
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PS3_Supporting, PS-Moderate, PP2, PP3, PP1_Moderate, PM1 -
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; Published functional studies using patch clamp assays in transfected Chinese hamster ovary (CHO) cells and Xenopus oocytes suggest that the G584S mutant channel causes a loss of the rapid delayed rectifier current due to trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016); Reported as a pathogenic/likely pathogenic variant in ClinVar (ClinVar Variant ID#67261; ClinVar); This variant is associated with the following publications: (PMID: 21440677, 27807201, 24606995, 22581653, 31447099, 15176425, 20659946, 20566482, 22949429, 25417810, 25649125, 26187847, 26669661, 19490267, 26958806, 19716085, 10862094, 23098067, 15840476, 10973849, 10483966, 19841300, 31358886, 28431243, 32048431, 34319147, 33087929) -
Congenital long QT syndrome Pathogenic:1Other:1
The p.Gly584Ser variant in KCNH2 has been reported in 4 individuals with long QT syndrome, segregated with disease in at least 11 affected relatives from 2 families (Swan 1999, Laitinen 2000, Zhao 2009, Giudicessi 2012, and Li 2015), and has also been reported by other clinical laboratories in ClinVar (Variation ID: 67261). In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009). This variant was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pathogenic. -
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10483966;PMID:10862094;PMID:10973849;PMID:15840476;PMID:19490267;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Short QT syndrome type 1 Pathogenic:1
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Long QT syndrome Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 584 of the KCNH2 protein (p.Gly584Ser). This variant is present in population databases (rs199473428, gnomAD 0.002%). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 10862094, 10973849, 19490267, 22949429, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67261). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 19490267). For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.G584S variant (also known as c.1750G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1750. The glycine at codon 584 is replaced by serine, an amino acid with similar properties, and is located in the S5/pore transmembrane spanning region. This alteration has been detected in long QT syndrome (LQTS) cohorts, a sudden cardiac arrest/death cohort, and cohorts referred for LQTS genetic testing with varying levels of clinical detail (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Christiansen M et al. BMC Med Genet. 2014;15:31; Li MH et al. Hum Genomics. 2015;9:15; Nakajima T et al. Circ J. 2015;79(6):1185-92). This alteration has been reported to segregate with disease in a family with symptomatic individuals and members with moderate QTc prolongation where, overall, carriers had longer QT intervals than non-carriers; however, some individuals with QT prolongation were not indicated as carriers of this alteration, suggesting that this alteration is associated with reduced phenotypic penetrance (Kerr SM et al. Sci Rep, 2019 Jul;9:10964; Swan H et al. J Am. Coll Cardiol. 1999;34:823-9; Laitinen P et al. Hum Mutat. 2000;15:580-1). In vitro functional studies have suggested this alteration may have some impact on channel function or protein trafficking (Zhao JT et al. J Cardiovasc Electrophysiol. 2009;20:923-30; Perry MD et al. J Physiol Lond. 2016;594:4031-49). Internal analysis indicates this alteration may be structurally disruptive (Wang W et al. Cell. 2017;169(3):422-430.e10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Pathogenic:1
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Cardiac arrhythmia Pathogenic:1
This missense variant replaces glycine with serine at codon 584 in the extracellular linker region between transmembrane domain S5 and pore-forming region 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. Experimental functional studies have shown that the mutant protein carrying this variant traffics to the cell membrane normally but has moderate impact on the channel function (PMID: 19490267, 26958806). This variant has been reported to segregate with long QT syndrome in a large multigenerational family (PMID: 19490267). This variant has also been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 10862094, 10973849, 22949429, 23098067, 24606995, 25925977). This variant has been identified in 2/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at