Submissions for variant NM_000238.4(KCNH2):c.100del (p.Ala34fs)

dbSNP: rs794728506

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001842863	SCV000234369	pathogenic	Cardiac arrhythmia	2011-10-16	criteria provided, single submitter	clinical testing	The c.100delG mutation in the KCNH2 gene has been reported previously in association with LQTS, and this mutation was absent from 2,600 control alleles. The c.100delG mutation causes a shift in reading frame starting at codon Alanine 34, changing it to a Leucine, and creates a premature stop codon at position 26 of the new reading frame, denoted p.Ala34LeufsX26. This mutation is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382672	SCV001581567	pathogenic	Long QT syndrome	2024-07-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala34Leufs*26) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 200805). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002433801	SCV002748153	pathogenic	Cardiovascular phenotype	2019-02-12	criteria provided, single submitter	clinical testing	The c.100delG pathogenic mutation, located in coding exon 2 of the KCNH2 gene, results from a deletion of one nucleotide at nucleotide position 100, causing a translational frameshift with a predicted alternate stop codon (p.A34Lfs*26). In a study of long QT syndrome clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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.