Description
This missense variant replaces arginine with histidine at codon 1632 of the SCN5A protein. This variant is also known as p.Arg1631His in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region (a.a.1530-1771) in the transmembrane domain DIV. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). In vitro functional studies have shown that this variant leads to profound impairment in channel function (PMID: 14523039, 20539757, 32533946). This variant has been reported in at least eight individuals affected with Brugada syndrome from five families (PMID: 24948852, 28781330, 29709101, 32893267, 37061847), in two young individuals affected with sick sinus syndrome, one of which was compound heterozygous for this variant and another pathogenic variant (PMID: 14523039, 34539730), and in two infants affected with sudden unexpected death (PMID: 35027292, Clinvar SCV002030070.1). It has been shown that this variant segregates with SCN5A-related phenotypes in one of the families including four carriers who were affected with Brugada syndrome, sick sinus syndrome, or progressive familial heart block (PMID: 24948852). This variant has been identified in 2/251374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1632Cys, is known to be pathogenic (Clinvar variation ID 242199), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
