ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4867C>T (p.Arg1623Ter) (rs137854613)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183087 SCV000235497 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing The R1623X variant in the SCN5A gene has been reported as a pathogenic variant (Benson et al., 2003; Makiyama et al., 2005; Gui et al., 2010). Benson et al. (2003) described the R1623X variant in a pediatric patient with congenital sick sinus syndrome who also harbored the T220I in the SCN5A gene. R1623X was present in the proband's mother, maternal aunt and maternal grandmother, all of whom were diagnosed with sub-clinical first degree heart block. R1623X was absent from 150 control alleles (Benson et al., 2003). Makiyama et al. (2005) identified R1623X in a 65 year-old Japanese individual diagnosed with Brugada syndrome and sick sinus syndrome, and was absent from 220 Japanese control alleles. Functional studies demonstrated no inward sodium current, indicating this variant results in a non-functional sodium channel (Makiyama et al., 2005; Gui et al., 2010). R1623X is predicted to cause loss of normal protein function by protein truncation. Other nonsense variants in the SCN5A gene have been reported in association with arrhythmia (Stenson et al., 2014). Furthermore, the R1623X pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R1623X in the SCN5A gene is interpreted as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000183087 SCV000343486 pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
Baylor-Hopkins Center for Mendelian Genomics,Johns Hopkins University RCV000465149 SCV000541078 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy criteria provided, single submitter research
Ambry Genetics RCV000622049 SCV000737901 pathogenic Cardiovascular phenotype 2019-04-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV001055137 SCV001219509 pathogenic Brugada syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Arg1623*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acids of the SCN5A protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with bradychardia or Brugada syndrome (PMID: 29574140, 14523039, 16325048). ClinVar contains an entry for this variant (Variation ID: 9374). This variant has been reported to affect SCN5A protein function (PMID: 14523039, 20539757, 16325048). This variant disrupts the C-terminus of the SCN5A protein. Other variant(s) that disrupt this region (p.Arg1629*) have been determined to be pathogenic (PMID: 25829473, 20129283, 25829473, 18361072). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color RCV001188430 SCV001355489 pathogenic Arrhythmia 2019-10-07 criteria provided, single submitter clinical testing
OMIM RCV000009968 SCV000030189 pathogenic Sick sinus syndrome 1, autosomal recessive 2003-10-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477950 SCV000536699 pathogenic Long QT syndrome 3 2014-10-31 no assertion criteria provided research

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