Submissions for variant NM_000335.5(SCN5A):c.283G>A (p.Val95Ile)

dbSNP: rs199473054

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455416	SCV000540281	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 3 papers in HGMD, classified as DM related to Brugada syndrome. It has been seen in affected and unaffected patients. It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (in 2013).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182923	SCV000939697	uncertain significance	not provided	2024-10-24	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 95 of the SCN5A protein (p.Val95Ile). This variant is present in population databases (rs199473054, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome or left ventricular noncompaction cardiomyopathy (PMID: 20877689, 31397097, 33500567). ClinVar contains an entry for this variant (Variation ID: 67761). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 23805106). 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.
Mendelics	RCV000987244	SCV001136494	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842317	SCV001352006	uncertain significance	Cardiac arrhythmia	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 95 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). An experimental functional study has shown that this variant does not change sodium channel function in vitro (PMID: 23805106). This variant has been identified in an individual affected with Brugada syndrome (PMID: 17081365, 20877689), in an individual affected with sudden death (PMID: 24529773), and in another individual affected with left ventricular noncompaction (PMID: 33500567). This variant has been identified in 7/249414 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.
All of Us Research Program, National Institutes of Health	RCV001842317	SCV004826764	uncertain significance	Cardiac arrhythmia	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 95 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). An experimental functional study has shown that this variant does not change sodium channel function in vitro (PMID: 23805106). This variant has been identified in an individual affected with Brugada syndrome (PMID: 17081365, 20877689), in an individual affected with sudden death (PMID: 24529773), and in another individual affected with left ventricular noncompaction (PMID: 33500567). This variant has been identified in 7/249414 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.
Ambry Genetics	RCV004984668	SCV005501616	uncertain significance	Cardiovascular phenotype	2024-09-10	criteria provided, single submitter	clinical testing	The c.283G>A (p.V95I) alteration is located in exon 3 (coding exon 2) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 283, causing the valine (V) at amino acid position 95 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/249414) total alleles studied. The highest observed frequency was 0.017% (3/18028) of East Asian alleles. This variant was reported in multiple individuals with sudden unexplained or heart failure-related death, clinical features consistent with SCN5A-related arrhythmias and/or cardiomyopathy and/or a personal or family history of Brugada syndrome (Liang, 2010; Liu, 2014; Li, 2018; Amin, 2018; Mazzarotto, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058531	SCV000090051	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17081365;PMID:20877689). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx	RCV000182923	SCV000235318	likely pathogenic	not provided	2013-11-07	flagged submission	clinical testing	p.Val95Ile (GTA>ATA): c.283 G>A in exon 3 of the SCN5A gene (NM_198056.2) The Val95Ile variant in the SCN5A gene has been reported previously in one Chinese individual diagnosed with Brugada syndrome, who also harbored the Ala1649Val variant in SCN5A (Liang P et al., 2006). Both variants were inherited from this patient's father who was asymptomatic and had a normal ECG, however, suggesting that V95I may not be pathogenic (Liang P et al., 2006). Additionally, Val95Ile was reported in one individual from a cohort of 120 sudden adult death cases in the Han Chinese (Hou Y et al., 2013). Mutations in nearby residues (Phe93Ser, Ile94Ser, Arg104Gln) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Val95Ile variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, one in vitro functional study showed that this variant does not affect sodium channel function (Gutter C et al., 2013). In summary, Val95Ile is a good candidate for a disease-causing mutation. The variant is found in ARRHYTHMIA panel(s).