Brugada syndrome and cardiac sodium channel disease

Gene: SCN10A

Comment on phenotypes: This gene is also associated with Episodic pain syndrome, familial, 2 (615551)

Created: 2 Mar 2021, 11:58 a.m. | Last Modified: 2 Mar 2021, 11:58 a.m.

Panel Version: 2.22

Green List (high evidence)

Episodic pain syndrome, familial, 2 (OMIM 615551), PR Interval, variation in (OMIM %108980)

Created: 25 Mar 2019, 4:30 p.m.

Rare. Evidence for association SNP / polygenic contribution Largest study in Hu paper PMID:24998131. PMID:25691538. PMID:25691686. PMID:25053638. https://www.ncbi.nlm.nih.gov/pubmed/28407228?dopt=Abstract.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
Unknown

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

Comment on list classification: Due to new expert reviews and disputed evidence for this gene-disease causation, this gene has been demoted from Green to Red.

Created: 27 Feb 2019, 10 a.m.

This gene was given a validity classification of Disputed by the ClinGen validity curation group and is reflected by providing a Red review here.The gene-disease summary was downloaded on 20th Feb 2019.For the full report and publications see the ClinGen Gene Validity Curation for each gene here: https://search.clinicalgenome.org/kb/gene-validity/10161

Created: 20 Feb 2019, 2:47 p.m.

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Mode of inheritance
Disputed

Phenotypes
Brugada syndrome 1; MONDO_0011001

Red List (low evidence)

Gene currently tested on Manchester cardiac gene panel. Only class 1-3 variants detected to date. 85 variants listed on HGMD (accessed 29/01/2019). ClinGen Knowledge Base: disputed association with Brugada syndrome (accessed 29/01/2019).

Created: 14 Feb 2019, 1:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Episodic pain syndrome, familial, 2 (615551)

Publications

• 24998131
• 27761167

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: 2014 paper: Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

Created: 11 Feb 2016, 11:27 a.m.

Comment on list classification: On Manchester diagnostic panel

Created: 11 Feb 2016, 11:25 a.m.

Red List (low evidence)

On ClinVar just 1 variant in this gene is classified as pathogenic however it was detected in someone with episodic pain syndrome (not BS). All variants detected in Brugada syndrome (>100) classed as UV suggesting there is an absence of fundamental evidence that variants in this gene cause BS. Many of the variants detected in early reports of in this gene were later noted to have relatively high frequencies in populations therefore caution should be applied to previous case reports e.g. Hu et al 2014.

Created: 25 Jan 2019, 1:15 p.m.

Hu et al 2014 reported detecting variants in SCN10A in 16.7% of BrS probands. However this figure has not been replicated in other multicentre-cohorts (Behr et al 2015). Most of the variants reported by Hu et al represent rare variants <1% on ExAC however some are present in ExAC at frequencies of up to 15%. Therefore, most of these variants would not be classified as pathogenic according to current UK best practice.

Created: 3 Mar 2016, 10:24 a.m.