Submissions for variant NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=)

gnomAD frequency: 0.00001  dbSNP: rs754221948

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000253171	SCV000317855	likely pathogenic	Cardiovascular phenotype	2023-12-22	criteria provided, single submitter	clinical testing	The c.4719C>T variant (also known as p.G1573G) is located in coding exon 26 of the SCN5A gene This variant results from a C to T substitution at nucleotide position 4719. This nucleotide substitution does not change the glycine at codon 1573. This variant has been detected in several individuals reported to have Brugada syndrome, cardiac conduction system disorder, and arrhythmias (Amin AS et al. Europace, 2011 Jul;13:968-75; Bardai A et al. Eur Heart J, 2013 May;34:1506-16; van der Knijff-van Dortmont AL et al. Case Rep Anesthesiol, 2016 Sep;2016:9278409; Roberts JD et al. JACC Clin Electrophysiol, 2017 Mar;3:276-288; Walsh R et al. Genet Med, 2021 Jan;23:47-58; Pannone L et al. Heart Rhythm, 2022 Jun;19:945-951). RNA studies performed on patient-derived lymphocytes and utilizing minigene constructs have demonstrated that this alteration results in abnormal splicing, predicted to result in an in-frame loss of the last 32 amino acids of coding exon 26 (O'Neill MJ et al. Circ Genom Precis Med, 2022 Dec;15:e003782; Bardai A et al. Eur Heart J, 2013 May;34:1506-16). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000498820	SCV000589382	pathogenic	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Identified in patients with Brugada syndrome and cardiac conduction disease in published literature (PMID: 19843921, 23425522, 25399282, 27668095, 29759522); Published functional studies demonstrate a damaging effect on sodium channel function (PMID: 23425522); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31737537, 25525159, 23425522, 27668095, 25399282, 29759522, 30662450, 29709244, 35124229, 32893267, 37061847, 36197721, 19843921)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498820	SCV001201210	pathogenic	not provided	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change affects codon 1573 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 32 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs754221948, gnomAD 0.003%). This variant has been observed in individual(s) with SCN5A-related conditions (PMID: 19843921, 27668095, 29759522, 31737537). ClinVar contains an entry for this variant (Variation ID: 263423). Studies have shown that this variant results in the activation of a cryptic splice site in exon 27 (PMID: 23425522). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Asp1595His) have been determined to be pathogenic (PMID: 15671429; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001843024	SCV004361621	likely pathogenic	Cardiac arrhythmia	2023-09-08	criteria provided, single submitter	clinical testing	This synonymous variant causes a C>T nucleotide change in exon 27 of the SCN5A gene. This variant is also known as c.4716C>T based on a different transcript NM_000335. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 96 nucleotides upstream of the native intron 27 splice donor site. Minigene assays and RNA studies with lymphocytes from a carrier have shown that this cryptic donor site is used and normal splicing is completely abolished, resulting in an in-frame deletion of 32 amino acids in the transmembrane domain DIV (PMID: 23425522, 36197721). Another functional study has shown that this variant causes a complete loss of sodium channel currents (PMID: 23425522). This variant has been reported in four individuals from three families affected with Brugada syndrome (PMID: 19843921, 23425522, 32893267, 35124229), in two related individuals affected with cardiac conduction disturbances (PMID: 27668095), and in another individual affected with bundle branch reentrant ventricular tachycardia (PMID: 29759522). This variant has been identified in 2/249326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003999007	SCV004843397	likely pathogenic	Brugada syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This synonymous variant causes a C>T nucleotide change in exon 27 of the SCN5A gene. This variant is also known as c.4716C>T based on a different transcript NM_000335. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 96 nucleotides upstream of the native intron 27 splice donor site. Minigene assays and RNA studies with lymphocytes from a carrier have shown that this cryptic donor site is used and normal splicing is completely abolished, resulting in an in-frame deletion of 32 amino acids in the transmembrane domain DIV (PMID: 23425522, O'Neill et al. 2022 doi: https://doi.org/10.1101/2022.03.14.484344). A functional study has shown that this variant causes a complete loss of sodium channel currents (PMID: 23425522). This variant has been reported in four individuals from three families affected with Brugada syndrome (PMID: 19843921, 23425522, 32893267, 35124229), in two related individuals affected with cardiac conduction disturbances (PMID: 27668095), and in another individual affected with bundle branch reentrant ventricular tachycardia (PMID: 29759522). This variant has been identified in 2/249326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Roden Lab, Vanderbilt University Medical Center	RCV004698489	SCV005200422	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, 3-38554373-G-A 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 0.898; 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV001843024	SCV000805035	uncertain significance	Cardiac arrhythmia	2016-08-18	no assertion criteria provided	clinical testing