ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4850_4852del (rs749697698)

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Total submissions: 5
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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 likely pathogenic Brugada syndrome 2019-12-11 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.) 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.
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

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