Submissions for variant NM_000335.5(SCN5A):c.935-3C>G

dbSNP: rs766127222

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Roden Lab, Vanderbilt University Medical Center	RCV004698552	SCV005200438	likely pathogenic	Brugada syndrome 1		criteria provided, single submitter	research	We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38608217-G-C was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.964; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as LP using these collective data.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004698552	SCV005399468	likely pathogenic	Brugada syndrome 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Using patient cDNA, this variant has been functionally proven to cause exon 8 skipping and a shift in the reading frame of this protein, resulting in p.(Glu312Glyfs*10) (Centenary Institute, Molecular Cardiology Program). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same splice site is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic (DECIPHER). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001787293	SCV002029159	uncertain significance	Brugada syndrome	2021-08-30	no assertion criteria provided	clinical testing