Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003654175 | SCV000545017 | pathogenic | not provided | 2023-04-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11823453, 25348405, 26283144). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 9391). This missense change has been observed in individuals with sudden unexplained nocturnal death syndrome and Brugada syndrome (PMID: 11823453, 17697823, 20129283, 30193851). This variant is present in population databases (rs137854611, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 735 of the SCN5A protein (p.Ala735Val). |
| Color Diagnostics, |
RCV003591627 | SCV004361693 | likely pathogenic | Cardiac arrhythmia | 2023-07-12 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with valine at codon 735 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region (a.a. 718 - 9386) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that the variant affects sodium channel function (PMID: 11823453, 31371804). This variant has been reported in at least 7 unrelated individuals affected with Brugada syndrome (PMID: 17697823, 26921764, 28341781, 28491738, 29325976, 32893267, ClinVar SCV000545017.3), in an individual affected with cardiac sinus node dysfunction (PMID: 22795782), and in a few individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed to segregate with abnormal ECG findings in three individuals from a family affected with sudden unexplained nocturnal death syndrome, a disease allelic to Brugada syndrome (PMID: 11823453). This variant has been identified in 1/249112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| All of Us Research Program, |
RCV003996084 | SCV004827566 | likely pathogenic | Congenital long QT syndrome | 2023-05-31 | criteria provided, single submitter | clinical testing | The c.2204C>T (p.Ala735Val) variant in the SCN5A gene is located on the exon 14 and is predicted to replace alanine with valine at codon 735 (p.Ala735Val). The variant has been reported in multiple individuals with Brugada syndrome, in one individual with cardiac sinus node dysfunction and in one individual with dilated cardiomyopathy/other cardiac disease (PMID: 11823453, 17697823, 20129283, 22795782, 36129056, 28491738). The variant has been reported to segregate with Brugada syndrome in one family (PMID: 11823453). Electrophysiological experiments of this variant reported the negative functional impact (PMID: 11823453, 26283144). The variant is reported in ClinVar (ID: 9391). This variant is rare in the general population according to gnomAD (1/249112). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.943). Therefore, the c.2204C>T (p.Ala735Val) variant of SCN5A has been classified as likely pathogenic. |
| OMIM | RCV000009989 | SCV000030210 | pathogenic | Brugada syndrome 1 | 2002-02-01 | no assertion criteria provided | literature only | |
| Cardiovascular Biomedical Research Unit, |
RCV000058488 | SCV000090008 | not provided | Brugada syndrome | no assertion provided | literature only | This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11823453;PMID:20129283;PMID:22795782). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. |