Submissions for variant NM_000335.5(SCN5A):c.3214_3215inv (p.Glu1072Ser)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598842	SCV000710285	uncertain significance	not provided	2020-07-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as variant of uncertain significance but additional evidence is not available (ClinVar Variant ID #503982; Landrum et al., 2016); Deletion of two base pairs and insertion of two different base pairs, which leads to the replacement of a glutamic acid (E) residue with a serine (S) residue at codon position 1072, denoted as E1072S; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33221895)
Color Diagnostics, LLC DBA Color Health	RCV001841489	SCV001343146	uncertain significance	Cardiac arrhythmia	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant (also known as c.3214_3215delinsTC in published literature due to the use of alternate nomenclature) replaces glutamic acid with serine at codon 1072 of the SCN5A protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individual(s) affected with Brugada syndrome (PMID: 33221895, 36516610). This variant has not been identified 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	RCV000598842	SCV001401399	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 1072 of the SCN5A protein (p.Glu1072Ser). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 33221895). ClinVar contains an entry for this variant (Variation ID: 503982). 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.
Ambry Genetics	RCV002325138	SCV002610751	uncertain significance	Cardiovascular phenotype	2022-11-03	criteria provided, single submitter	clinical testing	The c.3214_3215delGAinsTC variant, located in coding exon 16 of the SCN5A gene, results from an in-frame deletion of GA and insertion of TC at nucleotide positions 3214 to 3215. This results in the substitution of the glutamic acid residue for a serine residue at codon 1072, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort; however, clinical details were limited (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002491229	SCV002778852	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	2021-11-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841489	SCV004833372	uncertain significance	Cardiac arrhythmia	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant (also known as c.3214_3215delinsTC in published literature due to the use of alternate nomenclature) replaces glutamic acid with serine at codon 1072 of the SCN5A protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individual(s) affected with Brugada syndrome (PMID: 33221895, 36516610). This variant has not been identified 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.