Submissions for variant NM_000335.5(SCN5A):c.1654G>T (p.Gly552Trp)

gnomAD frequency: 0.00005  dbSNP: rs3918389

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001255000	SCV000235380	uncertain significance	not provided	2025-03-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with an SCN5A-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 26746457, 25904541)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001255000	SCV000545014	uncertain significance	not provided	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 552 of the SCN5A protein (p.Gly552Trp). This variant is present in population databases (rs3918389, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201458). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842901	SCV001348369	uncertain significance	Cardiac arrhythmia	2024-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 552 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown that this variant does not change the channel function (Glazer et al. 2021, DOI: 10.1101/2021.03.30.21254549). This variant has been reported in an individual affected with Andersen-Tawil syndrome, who also carried a pathogenic variant in the KCNJ2 gene that could explain the observed phenotype (PMID: 31020160). This variant has also been reported in four individuals who did not have a clinical indication for arrhythmias, cardiomyopathy, or heart failure (Glazer et al. 2021, DOI: 10.1101/2021.03.30.21254549). This variant has been identified in 4/280438 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.
New York Genome Center	RCV004799193	SCV001431089	uncertain significance	Brugada syndrome 1; Long QT syndrome 3	2022-02-07	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001255000	SCV002503570	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399665	SCV002707081	uncertain significance	Cardiovascular phenotype	2023-12-19	criteria provided, single submitter	clinical testing	The p.G552W variant (also known as c.1654G>T), located in coding exon 11 of the SCN5A gene, results from a G to T substitution at nucleotide position 1654. The glycine at codon 552 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected in a control individual and in a cohort not selected for presence of cardiovascular disease; however, clinical details were limited (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Van Driest SL et al. JAMA, 2016 Jan;315:47-57). This variant also co-occurred with a reportedly de novo KCNJ2 variant in an individual with asymptomatic ventricular tachycardia, QTc prolongation, and features of Andersen-Tawil syndrome (Nguyen D et al. Eur Heart J Case Rep, 2018 Sep;2:yty083). This amino acid position is well conserved in available 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.
PreventionGenetics, part of Exact Sciences	RCV004528960	SCV004104831	uncertain significance	SCN5A-related disorder	2023-01-06	criteria provided, single submitter	clinical testing	The SCN5A c.1654G>T variant is predicted to result in the amino acid substitution p.Gly552Trp. This variant was reported in an individual with Andersen-Tawil syndrome; however, this individual also harbored a potentially causative de novo variant in KCNJ2 (Nguyen et al. 2018. PubMed ID: 31020160). This variant was also documented in a control individual in a large cohort study of arrhythmia-associated disorders (Table S1, Kapplingeret al. 2015. PubMed ID: 25904541). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645439-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001842901	SCV004819784	uncertain significance	Cardiac arrhythmia	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 552 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change the channel function (Glazer et al. 2021, DOI: 10.1101/2021.03.30.21254549). This variant has been reported in an individual affected with Andersen-Tawil syndrome, who also carried a pathogenic variant in the KCNJ2 gene that could explain the observed phenotype (PMID: 31020160). This variant has also been reported in four individuals who did not have a clinical indication for arrhythmias, cardiomyopathy, or heart failure (Glazer et al. 2021, DOI: 10.1101/2021.03.30.21254549). This variant has been identified in 4/280438 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.