ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2548_2549GT[3] (p.Phe851fs) (rs397514450)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183154 SCV000235570 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing The c.2550_2551dupGT pathogenic variant in the SCN5A gene has been previously reported in association with DCM, LQTS, and Brugada Syndrome (Olson et al., 2005; Kapplinger et al., 2009; Kapplinger et al., 2010). This variant was initially reported to segregate with disease in several individuals from a family with a history of DCM and/or arrhythmia such as monomorphic ventricular tachycardia, heart block, and left bundle branch block (Olson et al., 2005). The c.2550_2551dupGT variant was subsequently reported in two additional individuals who were referred for genetic testing for either LQTS or Brugada syndrome (Kapplinger et al., 2009; Kapplinger et al., 2010). Furthermore, this variant has been identified independently of additional cardiogenetic variants in several individuals referred for arrhythmia genetic testing at GeneDx. The c.2550_2551dupGT variant causes a shift in reading frame starting at codon phenylalanine 851, changing it to a cysteine, and creating a premature stop codon at position 19 of the new reading frame, denoted p.F851CfsX19. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Many other frameshift variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with Brugada syndrome, DCM, and other SCN5A-related disorders (Stenson et al., 2014), further indicating that loss of function is a mechanism of disease for this gene. Moreover, this variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).In summary, c.2550_2551dupGT in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000698158 SCV000826802 pathogenic Brugada syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe851Cysfs*19) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two relatives affected with dilated cardiomyopathy and ventricular tachycardia (PMID: 15671429). Additionally, this variant has been reported in an individual with a history of cardiac arrest and in an individual referred for SCN5A testing (PMID: 28600387, 19716085, 20129283). This variant is also described as 2550-2551insTG or 2552_2553dupGT  in the literature (PMID: 15671429, 19716085). ClinVar contains an entry for this variant (Variation ID: 201560). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.
Color RCV001181535 SCV001346707 pathogenic Arrhythmia 2019-11-25 criteria provided, single submitter clinical testing
OMIM RCV000010008 SCV000030229 pathogenic Dilated cardiomyopathy 1E 2005-01-26 no assertion criteria provided literature only

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