Submissions for variant NM_000238.4(KCNH2):c.453dup (p.Thr152fs)

dbSNP: rs761863251

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599277	SCV000709874	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	Frameshift 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; Published in vitro functional studies demonstrate this variant alone failed to generate potassium current and when expressed with WT, it may enhance the WT channel function (Caballero et al., 2017); however, it is unclear how these studies may translate to a pathogenic role in vivo; Reported in ClinVar (ClinVar Variant ID# 503669; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 32383558, 32048431, 20851114, 28049825, 28166811, 26669661, 19716085, 15840476, 10973849, 16922724)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631596	SCV000752678	pathogenic	Long QT syndrome	2022-08-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503669). This variant is also known as insC453–454* (P151fs/179) and c.453dup (p.Thr152fs). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10973849, 20851114, 28049825). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Thr152Hisfs*180) 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).
Ambry Genetics	RCV002331026	SCV002634166	pathogenic	Cardiovascular phenotype	2019-05-17	criteria provided, single submitter	clinical testing	The c.453dupC pathogenic mutation, located in coding exon 3 of the KCNH2 gene, results from a duplication of C at nucleotide position 453, causing a translational frameshift with a predicted alternate stop codon (p.T152Hfs*180). This mutation has been detected in long QT syndrome cohorts, and has been reported to segregate with disease in a family (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Millat G et al. Clin. Chim. Acta, 2011 Jan;412:203-7; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6; Caballero R et al. Proc. Natl. Acad. Sci. U.S.A., 2017 01;114:E416-E425). 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.
Mendelics	RCV000988003	SCV001137549	uncertain significance	Long QT syndrome 2	2019-05-28	flagged submission	clinical testing