Submissions for variant NM_000238.4(KCNH2):c.2230C>T (p.Arg744Ter)

dbSNP: rs189014161

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181843	SCV000234146	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease This variant is associated with the following publications: (PMID: 31018519, 33013630, 33304416, 31727422, 19716085, 25525159, 28775708, 26704558, 28363160, 11854117, 22338672, 19841298, 11802537)
Invitae	RCV000473013	SCV000543429	pathogenic	Long QT syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg744*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). ClinVar contains an entry for this variant (Variation ID: 180383). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000617781	SCV000737741	pathogenic	Cardiovascular phenotype	2020-11-05	criteria provided, single submitter	clinical testing	The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in LQTS genetic testing cohorts, and has shown segregation with disease in two families (Ko YL et al. J. Formos. Med. Assoc., 2001 Nov;100:767-71; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000157266	SCV002320699	pathogenic	Long QT syndrome 2	2021-06-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000157266	SCV002579514	pathogenic	Long QT syndrome 2	2021-08-06	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000157266	SCV003925753	pathogenic	Long QT syndrome 2	2023-05-23	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV000473013	SCV004021972	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PVS1_Strong, PP1_Strong, PM2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017439	SCV004848134	pathogenic	Congenital long QT syndrome	2018-07-25	criteria provided, single submitter	clinical testing	The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT syndrome (Ko 2001, Moss 2002, Schwartz 2009, Kapplinger 2009, Crotti 2012), and 1 individual with LQTS and Charcot-Marie-Tooth disease, who also carried a dup of 17p11.2 (Losito 2009). This variant segregated with LQTS in 13 relatives from multiple families. This variant has also been reported in ClinVar (Variation ID 180383) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 744, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, absence from controls, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate (Richards 2015).
Blueprint Genetics	RCV000157266	SCV000206996	pathogenic	Long QT syndrome 2	2014-08-29	no assertion criteria provided	clinical testing