ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1128G>A (p.Gln376=) (rs770047651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200566 SCV000255267 pathogenic Long QT syndrome 2020-07-13 criteria provided, single submitter clinical testing This sequence change falls at the last nucleotide of exon 5. It affects a highly conserved nucleotide near the donor splice site. This variant is present in population databases (rs770047651, ExAC <0.01%). This variant has been reported in individuals affected with long QT syndrome (LQTS) (PMID: 10973849, 11854117, and internal Invitae database) and in 3 individuals referred for testing for LQTS. However, these individuals were not phenotypically confirmed to have a clinical LQTS diagnosis (PMID: 15840476, 19716085) Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618780 SCV000737527 likely pathogenic Cardiovascular phenotype 2016-06-17 criteria provided, single submitter clinical testing The c.1128G>A variant (also known as p.Q376Q), located in coding exon 5 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1128. This nucleotide substitution does not change the at codon 376. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. This alteration was reported in multiple individuals with clinically diagnosed or suspected long-QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Steffensen AB et al. Sci Rep. 2015; 5:10009). Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (1/24042). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6489 samples (12978 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP, ESEfinder, and Human Splicing Finder (HSF; Desmet FO et al. Nucleic Acids Res. 2009 May;37(9):e67) splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001524117 SCV001733886 uncertain significance Arrhythmia 2020-11-10 criteria provided, single submitter clinical testing This synonymous variant causes a G to A substitution at the last nucleotide of exon 5 of the KCNH2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 10973849, 11854117, 25929701) and in several individuals suspected with long QT syndrome (PMID: 15840476, 19716085). This variant has also been reported in one individual affected with sudden cardiac death (PMID: 28794082). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223833 SCV000280116 likely pathogenic not provided 2011-08-26 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Gln376Gln Based on the information reviewed below, we classify it as likely disease causing. This specific variant has been reported in the literature in at least 4 unrelated individuals: 1 with a clinical diagnosis of LQTS (Splawski et al 2000) and 3 tested at Mayo Clinic’s Sudden Death Genomics Laboratory/Familion due to suspicion for LQTS (Tester et al 2005; Kapplinger et al 2009). This is predicted to be a splice site variant (it does not result in an amino acid change to the protein), which alters the last base of exon 5, immediately 5 prime of the canonical “GT” splice donor site. Splice site variation is an established form of disease-causing variation in the KCNH2 gene (HGMD professional version as of January 17, 2014). In silico analysis with 3 different splice algorithms predicts this variant to destroy the donor site at the exon 5/intron 5 junction, which may lead to abnormal gene splicing. In total the variant has been seen in 0/1500 published controls and 1/12,000 individuals from publicly available population datasets. There is no variation at this nucleic acid listed in the NHLBI Exome Sequencing Project dataset (, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this nucleotide listed in dbSNP ( or 1000 Genomes ( as of 6/2/2015. The variant is present in 1 European individual in the ExAC dataset, out of 5,518 Europeans total; it is not present in another 6,503 individuals of African, East Asian, South Asian, and Latino, and Other ancestry. It was not observed in published controls: 200 controls (Splawski et al 2000), 1300 controls (Kapplinger et al 2009; 47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, 6% Unknown/Other).

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