Submissions for variant NM_000238.4(KCNH2):c.3017del (p.Gly1006fs)

dbSNP: rs794728504

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182063	SCV000234366	pathogenic	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 15840476, 15851119, 12877697, 31361068)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461198	SCV000543476	pathogenic	Long QT syndrome	2021-09-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with KCNH2-related conditions (PMID: 12877697, 15840476). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Gly1006Alafs*51) 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).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001089526	SCV001244879	pathogenic	Long QT syndrome 2	2019-08-21	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227699	SCV003924213	pathogenic	Short QT syndrome type 1; Long QT syndrome 2	2021-03-30	criteria provided, single submitter	clinical testing	KCNH2 NM_000238.3 exon 13 p.Gly1006Alafs*51 (c.3017delG): This variant has been reported in the literature in at least 3 individuals with LQTS (Nemec 2003 PMID:12877697 ). This variant is not present in large control databases but is present in ClinVar (Variation ID:200799). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 51 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Hedley 2009 PMID:19862833). In summary, this variant is classified as pathogenic based on the data above.