Submissions for variant NM_000335.5(SCN5A):c.2182G>A (p.Val728Ile)

gnomAD frequency: 0.00002  dbSNP: rs958480279

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781842	SCV000920199	uncertain significance	not specified	2017-12-18	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.2182G>A (p.Val728Ile) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (IPR005821) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/246420 control chromosomes (gnomAD and Garca-Molina_2013) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001). This variant was reported in one patient with Brugada syndrome without strong evidence for causality (Garca-Molina_2013). Taken together, this variant is classified as VUS until additional evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001841974	SCV001349577	uncertain significance	Cardiac arrhythmia	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 22984773) and in an individual affected with early repolarization syndrome (PMID: 34649698). This variant has also been identified in 3/280656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001759475	SCV001556999	uncertain significance	not provided	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 728 of the SCN5A protein (p.Val728Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome and/or SCN5A-related conditions (PMID: 14985827, 22984773, 33221895, 36578016). ClinVar contains an entry for this variant (Variation ID: 633412). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001759475	SCV001987407	uncertain significance	not provided	2021-10-14	criteria provided, single submitter	clinical testing	Reported in a cohort of individuals with Brugada syndrome, however, patient-specific data were not provided (Ciconte et al., 2021); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 633412; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30662450, 26582918, 22984773, 33221895)
Ambry Genetics	RCV002424779	SCV002729379	uncertain significance	Cardiovascular phenotype	2020-03-16	criteria provided, single submitter	clinical testing	The p.V728I variant (also known as c.2182G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2182. The valine at codon 728 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an asymptomatic patient in a Brugada syndrome cohort (García-Molina E et al. Clin. Genet., 2013 Jun;83:530-8). This amino acid position is well conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487613	SCV002789666	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841974	SCV004821607	uncertain significance	Cardiac arrhythmia	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 22984773) and in an individual affected with early repolarization syndrome (PMID: 34649698). This variant has also been identified in 3/280656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254736	SCV001430818	uncertain significance	Sudden cardiac arrest	2020-04-07	no assertion criteria provided	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.