Submissions for variant NM_000335.5(SCN5A):c.4214G>A (p.Gly1405Glu)

dbSNP: rs199473609

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183063	SCV000235472	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Identified in at least two individuals referred for genetic testing for Brugada syndrome (Kapplinger et al., 2010); however, no clinical information was provided; 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 showed that p.(G1406E) resulted in a partial loss of peak current (Glazer et al., 2020); This variant is associated with the following publications: (PMID: 20129283, 30662450, 32569262, 31324802, 32533946)
Color Diagnostics, LLC DBA Color Health	RCV001842359	SCV001342759	uncertain significance	Cardiac arrhythmia	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 1406 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 2 individuals referred for Brugada syndrome genetic testing (PMID: 20129283). 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	RCV000183063	SCV004292661	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1406 of the SCN5A protein (p.Gly1406Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 20129283, 25904541, 32533946). ClinVar contains an entry for this variant (Variation ID: 67869). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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.
All of Us Research Program, National Institutes of Health	RCV001842359	SCV004832798	uncertain significance	Cardiac arrhythmia	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 1406 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 2 individuals referred for Brugada syndrome genetic testing (PMID: 20129283). 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058648	SCV000090168	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.