Submissions for variant NM_000335.5(SCN5A):c.5123C>T (p.Thr1708Met)

dbSNP: rs199473297

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183101	SCV000235511	uncertain significance	not provided	2022-08-04	criteria provided, single submitter	clinical testing	Reported in association with Brugada syndrome in several patients, however, many publications lack patient-specific clinical details and no segregation data are available (Yokokawa et al., 2007; Kapplinger et al., 2010; Calvo et al., 2015; Lakshmanadoss et al., 2016; Yamagata et al., 2017; Chen et al., 2019; Wijeyeratne et al., 2020; Ishikawa et al., 2021); 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; Published functional studies suggest a damaging effect with significant reduction in channel current (Glazer et al., 2020; Pearman et al., 2020; Ishikawa et al., 2021); This variant is associated with the following publications: (PMID: 19027780, 25460174, 30690642, 20129283, 27676163, 25904541, 28341781, 34219138, 33131149, 32533946, 30662450, 30193851, 33164571, 17697823)
Ambry Genetics	RCV000617525	SCV000737887	uncertain significance	Cardiovascular phenotype	2020-12-29	criteria provided, single submitter	clinical testing	The c.5126C>T (p.T1709M) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5126, causing the threonine (T) at amino acid position 1709 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183101	SCV000937421	likely pathogenic	not provided	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1709 of the SCN5A protein (p.Thr1709Met). This variant is present in population databases (rs199473297, gnomAD 0.0009%). This missense change has been observed in individuals with Brugada syndrome (PMID: 17697823, 20129283, 27676163, 30193851, 34461752, 36578016). ClinVar contains an entry for this variant (Variation ID: 67957). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946, 34219138). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001842378	SCV001357587	uncertain significance	Cardiac arrhythmia	2019-03-16	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces threonine with methionine at codon 1709 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individual affected with, or suspected of having, Brugada syndrome (PMID: 17697823, 20129283) and in an individual affected with overlapping Brugada syndrome and long QT syndrome phenotype (PMID: 27676163). This variant has been identified in 1/246270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
All of Us Research Program, National Institutes of Health	RCV000058742	SCV005428233	likely pathogenic	Brugada syndrome	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1709 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a.1524-1772). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a reduction of sodium channel current in transfected cells (PMID: 32533946, 34219138). This variant has been reported in at least 7 unrelated individuals affected with Brugada syndrome (PMID: 17697823, 20129283, 25460174, 26743238, 28341781, 30193851, 30690642, 32893267, 34461752), in an individual affected with fever-induced Brugada syndrome (PMID: 36516610), and in an individual affected with overlapping Brugada syndrome and long QT syndrome phenotype (PMID: 27676163). This variant has been identified in 1/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058742	SCV000090262	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17697823;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000058742	SCV001430844	likely pathogenic	Brugada syndrome	2020-02-12	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000183101	SCV001740256	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000183101	SCV001929718	uncertain significance	not provided		no assertion criteria provided	clinical testing