Submissions for variant NM_000238.4(KCNH2):c.1979C>T (p.Ser660Leu)

gnomAD frequency: 0.00001  dbSNP: rs199472979

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181833	SCV000234136	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although functional studies did not identify a trafficking defect when S660L mutant channel was co-expressed with wild type channel in HEK293 cells, the biophysical properties of the mutant channels were not investigated (PMID: 25417810); This variant is associated with the following publications: (PMID: 19862833, 23158531, 21737021, 16414944, 19716085, 28488422, 31737537, 36339618, 25417810)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468503	SCV000543477	likely pathogenic	Long QT syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 660 of the KCNH2 protein (p.Ser660Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 16414944, 19716085, 31737537; Invitae). ClinVar contains an entry for this variant (Variation ID: 67352). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 25417810). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000621327	SCV000737497	pathogenic	Cardiovascular phenotype	2023-06-01	criteria provided, single submitter	clinical testing	The p.S660L pathogenic mutation (also known as c.1979C>T), located in coding exon 8 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1979. The serine at codon 660 is replaced by leucine, an amino acid with dissimilar properties. This mutation was reported in several individuals with long QT syndrome (LQTS) (Napolitano C et al. JAMA. 2005;294(23):2975-80). Additionally, this mutation was described as likely de novo in a sporadic case of LQTS and observed to segregate with disease in multiple individuals in two other families (Napolitano C, personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000851290	SCV000993562	likely pathogenic	Long QT syndrome 2	2019-06-08	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000058072	SCV001653075	likely pathogenic	Congenital long QT syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The p.Ser660Leu variant in KCNH2 has been previously reported in at least 6 individuals with Long QT syndrome (LQTS) and in 5 individuals referred for LQTS genetic testing (Crotti 2012 PMID: 23158531, Kapplinger 2009 PMID: 19716085, Napolitano 2005 PMID: 16414944, Nunn 2011 PMID: 21737021, Marschall 2019 PMID: 31737537, GeneDx pers. comm.). It has also been reported by other clinical laboratories in ClinVar (Variation ID 67352), including one submission that states the variant was found to be de novo in an individual with LQTS, and that the variant segregated in five affected relatives across 2 families (SCV000234136.9). This variant is absent from large population studies. An in vitro functional study did not find that this variant was associated with abnormal trafficking compared to wild-type (Anderson 2014 PMID 25417810); however, it is unclear how the variant affects the biophysical properties of the channel. Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM6, PP1_Moderate, PP3, PS4_Moderate, PM2_Supporting.
All of Us Research Program, National Institutes of Health	RCV000468503	SCV004830770	likely pathogenic	Long QT syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 660 of C-terminal cytoplasmic domain of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant has no significant impact on the trafficking of KCNH2 protein in transfected HEK293 cells (PMID: 25417810). This variant has been observed in about ten individuals affected with or suspected of long QT syndrome (PMID: 16414944, 19716085, 23158531, 28488422, ClinVar SCV000737497.4, SCV000543477.8, SCV001653075.1) and reported to be a de novo occurrence in one of them and segregate with disease in two families (ClinVar SCV000737497.4). This variant has also been reported in an individual with J-point elevation and prolonged QTc interval in electrocardiogram, who had a first-degree relative that died of sudden arrhythmic death syndrome (PMID: 21737021). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058072	SCV000089592	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.