Submissions for variant NM_000335.5(SCN5A):c.1859G>A (p.Arg620His)

gnomAD frequency: 0.00003  dbSNP: rs746504626

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841157	SCV001359788	uncertain significance	Cardiac arrhythmia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 620 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has no significant impact on channel current (PMID: 23424222). This variant has been reported in an individual affected with Brugada syndrome and in an unaffected family member (PMID: 27810048). This variant has been identified in 7/222678 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541290	SCV001490896	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 620 of the SCN5A protein (p.Arg620His). This variant is present in population databases (rs746504626, gnomAD 0.008%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 23424222, 32533946). ClinVar contains an entry for this variant (Variation ID: 928169). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 23424222, 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.
Fulgent Genetics, Fulgent Genetics	RCV002484054	SCV002794092	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	2021-09-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841157	SCV004832647	uncertain significance	Cardiac arrhythmia	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 620 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has no significant impact on channel current (PMID: 23424222). This variant has been reported in an individual affected with Brugada syndrome and in an unaffected family member (PMID: 27810048). This variant has been identified in 7/222678 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.