ClinVar Genomic variation as it relates to human health

This sequence change affects a donor splice site in intron 5 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Brugada syndrome (PMID: 20129283, 29709101). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201427). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The c.611+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the SCN5A gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been described in individuals and families with Brugada syndrome; of note, at least one individual had a co-occurring SCN5A alteration also detected, and one reportedly unaffected carrier was also described (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Robyns T et al. Ann Noninvasive Electrocardiol, 2018 09;23:e12548; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298) This variant has also been observed in a long QT syndrome cohort; however, clinical details were limited (Christiansen M et al. BMC Med Genet, 2014 Mar;15:31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Identified in patients with Long QT syndrome and Brugada syndrome referred for genetic testing at GeneDx and in published literature (PMID: 20129283, 24606995, 29709101, 30690642, 31737537, 34461752); Not observed in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20129283, 25525159, 31737537, 24606995, 29709101, 30690642, 34461752)

This variant (also known as IVS5+1G>A in published literature) causes a G to A nucleotide substitution at the +1 position of intron 5 of the SCN5A gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in about ten individuals affected with Brugada syndrome (PMID: 20129283, 29709101, 29884292, 32893267), in two young individuals affected with sinus node dysfunction (PMID: 26111534, 37746560), in an individual affected with mitral valve dilatation (PMID: 36143288), and in an individual affected with long QT syndrome (PMID 24606995). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with Brugada syndrome and long QT syndrome (PMID: 20129283, 24606995, 29709101, 29884292, 32893267). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

Variant interpreted as Pathogenic and reported on 06-19-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.