ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1597G>A (p.Gly533Ser) (rs41314354)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171755 SCV000055201 likely benign Brugada syndrome 2013-06-24 criteria provided, single submitter research
Invitae RCV001083512 SCV000283974 likely benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000777752 SCV000913715 likely benign Arrhythmia 2018-10-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194444 SCV001364007 benign not specified 2019-03-31 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2617G>A (p.Gly873Ser) 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 0.00027 in 278760 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0023 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Verkerk et al. (2005) reported c.2617G>A in a patient affected with Brugada syndrome and carried out functional assessments to determine the effect of the variant on protein function. A a negative shift of voltage-dependent inactivation resulting in increased rectification was noted and increased transient peak currents of the ventricular action potential were described. These results do not support an association of this finding with the established pathophysiology of disease in LQT2 (decreased rapid delayed rectifier potassium current) and Brugada syndrome (KCNH2 is not widely recognized as a gene causative of Brugada syndrome). Therefore, these findings do not provide unequivocal conclusions about association of the variant with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058144 SCV000089664 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:16487223;PMID:14661677;PMID:16043162;PMID:19841300).

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