Submissions for variant NM_000335.5(SCN5A):c.4279G>T (p.Ala1427Ser)

gnomAD frequency: 0.00003  dbSNP: rs200034939

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155812	SCV000205523	uncertain significance	not specified	2014-11-06	criteria provided, single submitter	clinical testing	The p.Ala1428Ser variant in SCN5A has been reported in 1 a 13 year old individua l with Long QT syndrome (likely of Japanese ancestry) and 1 Italian individual w ith Brugada syndrome (Sommariva 2013, Yoshikane 2013). In the family reported by Yoshikane et al. this variant was also present in the reportedly unaffected mot her and aunt, raising the possibility that it has a milder effect or is benign. This variant has been identified in 1/194 Han Chinese chromosomes by the 1000 Ge nomes Project (dbSNP rs200034939) and in 3/8766 East Asian chromosomes by the Ex ome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that it may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala1428Ser variant is uncertain.
GeneDx	RCV000183069	SCV000235478	uncertain significance	not provided	2020-01-31	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26136871, 23321620, 23237912, 27707468, 25864170, 26332594, 28341781, 29728395, 29806494, 30662066, 30203441, 30193851, 32619740, 33131149)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183069	SCV000255232	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1428 of the SCN5A protein (p.Ala1428Ser). This variant is present in population databases (rs200034939, gnomAD 0.04%). This missense change has been observed in individuals with Brugada syndrome (BrS) (PMID: 23321620, 26136871, 28341781, 30193851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179030). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 26136871). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000987202	SCV001136451	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842488	SCV001355710	uncertain significance	Cardiac arrhythmia	2023-04-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1428 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIII. Rare nontruncating variants in transmembrane and linker regions have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three unrelated individuals affected with Brugada syndrome and in one individual suspected of having Brugada syndrome (PMID: 23321620, 32619740, 32893267, 33641026, 36354768). This variant has also been reported in an individual affected with long QT syndrome (PMID: 23237912). These individuals were mostly East Asian. This variant has been identified in 8/250628 chromosomes (8/18390 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Because of the relatively high variant allele frequency in the East Asian population, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842488	SCV004815150	uncertain significance	Cardiac arrhythmia	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1428 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIII. Rare nontruncating variants in transmembrane and linker regions have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three unrelated individuals affected with Brugada syndrome and in one individual suspected of having Brugada syndrome (PMID: 23321620, 32619740, 32893267, 33641026, 36354768). This variant has also been reported in an individual affected with long QT syndrome (PMID: 23237912). These individuals were mostly East Asian. This variant has been identified in 8/250628 chromosomes (8/18390 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Because of the relatively high variant allele frequency in the East Asian population, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Roden Lab, Vanderbilt University Medical Center	RCV000987202	SCV005200455	uncertain significance	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, 3-38557248-C-A was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.00000657 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.268724; 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 VUS using these collective data.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000199660	SCV002029156	uncertain significance	Brugada syndrome	2021-08-16	no assertion criteria provided	clinical testing