ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4844TCT[1] (p.Phe1616del) (rs749697698)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183166 SCV000235582 likely pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The c.4850_4852delTCT variant has been previously reported in multiple individuals in association with LQTS, Brugada syndrome (BrS) and sick sinus syndrome (SSS) (Splawski et al., 2000; Benson et al., 2003; Liang et al., 2006; Zellerhoff et al., 2009; Liang et al., 2010; Crotti et al., 2012; Tan et al., 2014; Itoh et al., 2016). In two patients, an additional variant was also identified; an individual with SSS was compound heterozygous for c.4850_4852delTCT and the R1623H variant in the SCN5A gene, and an individual with LQTS also harbored the R518X nonsense variant in the KCNQ1 gene (Benson et al., 2003; Tan et al., 2014). Additionally, while segregation data are limited, this variant has also been observed at GeneDx in other families in association with LQTS, BrS and SSS. This variant causes a deletion of a single phenylalanine residue at position 1617, denoted p.Phe1617del, which is located in the short extracellular loop between segments S3 and S4 in the repeat domain IV (Benson et al., 2003). Furthermore, functional studies in mammalian cultured cells have demonstrated that this variant alters sodium current kinetics and may cause both gain-of-function and loss-of-function effects on sodium currents, depending on the membrane potential (Benson et al., 2003; Chen et al., 2005; Gui et al., 2010). Finally, the c.4850_4852delTCT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Blueprint Genetics RCV000208172 SCV000264218 likely pathogenic Long QT syndrome 2015-05-11 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000240624 SCV000299257 likely pathogenic Long QT syndrome 3 2016-06-29 criteria provided, single submitter clinical testing This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server). In addition, the variant has been reported previously in individuals with longQT syndrome. The variant results in an inframe deletion of one amino acid and thus reduces the length of the protein. Functional studies demonstrated that this variant alters sodium current kinetics (PMID: 14523039; PMID: 15665061).
Invitae RCV000474854 SCV000545078 pathogenic Brugada syndrome 2020-06-29 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 28 of the SCN5A mRNA (c.4850_4852delTCT). This leads to the deletion of 1 amino acid residue in the SCN5A protein (p.Phe1617del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749697698, ExAC 0.009%). This variant has been reported in a family affected with long QT syndrome (PMID: 10973849), an individual referred for long QT syndrome genetic testing (PMID: 19716085), individuals with suspected Brugada syndrome (PMID: 17081365, 22840528), and an individual with sick sinus syndrome (PMID: 14523039). Furthermore, this variant has been reported to be a founder mutation in individuals with German-Dutch descent and has been shown to segregate with long-QT syndrome and conduction disease (PMID: 28782696). ClinVar contains an entry for this variant (Variation ID: 201572). Experimental studies have shown that this deletion may affect the activation of the sodium channel (PMID: 15665061, 20448214) For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000240624 SCV000805140 pathogenic Long QT syndrome 3 2018-02-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000183166 SCV001447215 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000183166 SCV001711934 pathogenic not provided 2021-05-13 criteria provided, single submitter clinical testing This variant (rs749697698) is rare in a large population database (5/250930 total alleles, 0.002%, no homozygotes) and has an entry in ClinVar. This variant has been reported in families and/or individuals with autosomal dominant long QT syndrome-3 or Brugada syndrome-1. This variant causes a deletion of a single phenylalanine residue in the SCNA5 protein, which is located in the short extracellular loop between segments S3 and S4 in the repeat domain IV. Functional studies using cultured mammalian cells have demonstrated that this variant alters sodium current kinetics and may cause either an increase or decrease in sodium currents, depending on the membrane potential. We consider this variant to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000183166 SCV001713284 pathogenic not provided 2019-10-14 criteria provided, single submitter clinical testing PS3, PP1_Strong PM4
Color Health, Inc RCV001524476 SCV001734337 likely pathogenic Arrhythmia 2020-12-18 criteria provided, single submitter clinical testing This variant causes an in-frame deletion of one amino acid in the transmembrane domain DIV of the SCN5A protein. Functional studies have shown that the mutant channel caused reduced peak sodium current density and impaired fast inactivation, resulting in a net loss of channel function (PMID: 14523039, 15665061, 20448214). This variant has been reported to segregate with long QT syndrome in individuals from a 16-generation Dutch-German pedigree (PMID: 28782696). Additionally, this variant has been reported in one individual affected with long QT syndrome (PMID: 32454217), a family affected with Romano-Ward syndrome (PMID: 10973849), one individual affected with congenital sick sinus syndrome (PMID: 14523039), and one individual with or suspected with Brugada syndrome (PMID: 22840528). This variant has been identified in 5/250930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.