7-150947864-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000238.4(KCNH2):c.2707G>A(p.Gly903Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,530,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2707G>A | p.Gly903Arg | missense_variant | Exon 12 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2707G>A | p.Gly903Arg | missense_variant | Exon 12 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1687G>A | p.Gly563Arg | missense_variant | Exon 8 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3540G>A | non_coding_transcript_exon_variant | Exon 10 of 13 |
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000143 AC: 18AN: 126304Hom.: 0 AF XY: 0.000202 AC XY: 14AN XY: 69230
GnomAD4 exome AF: 0.000347 AC: 478AN: 1377834Hom.: 0 Cov.: 36 AF XY: 0.000372 AC XY: 253AN XY: 679646
GnomAD4 genome AF: 0.000256 AC: 39AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Identified in patients with LQTS and sudden death referred for genetic testing at GeneDx and in published literature (PMID: 19716085, 34002542, 27000522); One in vitro functional study suggests p.(G903R) may alter the kinetic properties of potassium channel; however, another in vitro functional study suggests this variant has minimal effect on channel function (PMID: 34002542, 31557540); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28988457, 19716085, 26746457, 32048431, 31737537, 30847666, 34002542, 26582918, 36860515, 27000522, 37589201, 31557540) -
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not specified Uncertain:2
Variant summary: KCNH2 c.2707G>A (p.Gly903Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 126304 control chromosomes. The observed variant frequency is approximately 1.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing long QT syndrome (0.0001), suggesting that the variant may be benign. c.2707G>A has been reported in the literature in at least 5 individuals who underwent genetic testing for arrhythmia, at least one individual with epilepsy, and at least one individual who died suddenly as well as a family member with a prolonged QT interval (eg., Kapplinger_2009, Cann_2016, Marschall_2019, van Lint_2019, Soh_2021). However, these data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function; one study demonstrates the variant has a mild effect on channel deactivation kinetics, however both studies conclude there is no effect on protein expression levels when compared to wild type (Ng_2020, Soh_2021). The following publications have been ascertained in the context of this evaluation (PMID: 27000522, 19716085, 31737537, 31557540, 34002542, 30847666). ClinVar contains an entry for this variant (Variation ID: 67428). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 3 patients referred for LQTS genetic testing. The variant is not in ExAC. It is classified with 1 star in ClinVar as VUS by GeneDx. -
Long QT syndrome Uncertain:2
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 903 of the KCNH2 protein (p.Gly903Arg). This variant is present in population databases (rs199473669, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome or Brugada syndrome (PMID: 19716085, 27000522). ClinVar contains an entry for this variant (Variation ID: 67428). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 31557540). 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. -
This missense variant replaces glycine with arginine at codon 903 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). Functional studies have shown that this variant does not change protein expression levels and has no or a mild impact on the potassium channel function (PMID: 31557540, 34002542). This variant has been reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085) and in an individual affected with epilepsy (PMID: 34002542). This variant has also been reported in individuals affected with sudden death, and in family members who had prolonged QTc interval (PMID: 27000522, 37449562, 37589201). This variant has been reported at a frequency of 0.097% in a large population study, demonstrating no significant correlation with prolonged QTc intervals in the Icelandic population (PMID: 37449562). This variant has been identified in 19/157684 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. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:2
The c.2707G>A variant has previously been reported in literature as Variant of Uncertain Significance [PMID: 19716085, 28988457, 31737537, 30847666, 32048431] and it has also been deposited in ClinVar [ClinVar ID: 67428] as Variant of Uncertain Significance by multiple submitters. The c.2707G>A variant is observed in 127 alleles (~0.027% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant inthe populations represented in those databases, which might include individuals with cardiac phenotypes. The c.2707G>A variant is located in exon 12 of this 15-exon gene, and predicted to replace an evolutionarily conserved glycine amino acid with arginine at position 903 in the second disordered region of the encoded protein [UniProtKB ID: Q12809]. Patch-clamp assays with transfected HEK293 cell lines demonstrated modestly accelerated rates of channel deactivation for p.(Gly903Arg) variant compared to wild-type allele [PMID: 31557540]. In silico predictions are also moderately in favor of damaging effect for the p.(Gly903Arg) variant (CADD v1.6 =23.3, REVEL = 0.745). Based on available evidence this c.2707G>A p.(Gly903Arg) variant identified in KCNH2 is classified as a Variant of Uncertain Significance. -
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Cardiac arrhythmia Uncertain:1
This missense variant replaces glycine with arginine at codon 903 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). Functional studies have shown that this variant does not change protein expression levels and has no or a mild impact on the potassium channel function (PMID: 31557540, 34002542). This variant has been reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085) and in an individual affected with epilepsy (PMID: 34002542). This variant has also been reported in an individual affected with sudden death, and in a family member who had prolonged QTc (PMID: 27000522). This variant has been identified in 19/157684 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. -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Congenital long QT syndrome Other:1
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