Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000602538 | SCV000712425 | uncertain significance | not specified | 2016-09-21 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr630Thr variant in SCN5A has been reported in 4 individuals with Brugada syndrome (Kapp linger 2010, Chockalingam 2012) and was absent from large population studies. Th is variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational predictions suggest a possible effect but functi onal assays would be needed to confirm this. Splice variants often lead to loss of function, which is an established mechanism for this gene for Brugada syndrom e. In summary, the absence from large populations, occurrence in several proband s with a consistent phenotype and location of the variant provide some support f or a role in disease; however, without additional evidence the clinical signific ance of the p.Thr630Thr variant remains uncertain. |
| Ambry Genetics | RCV000618308 | SCV000737544 | likely pathogenic | Cardiovascular phenotype | 2023-07-12 | criteria provided, single submitter | clinical testing | The c.1890G>A variant (also known as p.T630T), located in coding exon 11 of the SCN5A gene. This variant results from a G to A substitution at nucleotide position 1890. This nucleotide substitution does not change the threonine at codon 630. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This variant was observed in individuals reported to have Brugada syndrome; however, clinical details were limited (Kapplinger JD, Heart Rhythm 2010 Jan; 7:33-46; Chockalingam P, Heart Rhythm 2012 Dec; 9:1986-92). This nucleotide position is well conserved in available vertebrate species; however, A is the reference nucleotide in other vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001841492 | SCV001361002 | likely pathogenic | Cardiac arrhythmia | 2019-10-29 | criteria provided, single submitter | clinical testing | Variant summary: SCN5A c.1890G>A (p.Thr630Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts that the variant abolishes a 5' splicing donor site, while four predict that the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.7e-06 in 174574 control chromosomes (gnomAD). c.1890G>A has been reported in the literature in individuals affected with Arrhythmia [e.g. Kapplinger_2010 (Brugada Syndrome), Chockalingham_2012, Baruteau_2018]. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cites the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV003541209 | SCV001574354 | pathogenic | not provided | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change affects codon 630 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 22885917, 30193851, 33221895). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505275). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). For these reasons, this variant has been classified as Pathogenic. |
| Roden Lab, |
RCV002298705 | SCV002588734 | likely pathogenic | Brugada syndrome 1 | 2022-10-05 | criteria provided, single submitter | research | The synonymous SCN5A variant c.1890G>A was observed in 1 case of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter RNA splicing. A minigene functional assay showed aberrant splicing induced by the variant. These findings support the classification of this variant as Likely Pathogenic |