Submissions for variant NM_000335.5(SCN5A):c.1373G>A (p.Arg458His)

gnomAD frequency: 0.00001  dbSNP: rs373692157

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182970	SCV000235368	uncertain significance	not provided	2012-07-28	criteria provided, single submitter	clinical testing	p.Arg458His (CGT>CAT):c.1373 G>A in exon 11 of the SCN5A gene (NM_198056.2) The Arg458His variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg458His results in a conservative substitution of one positively charged amino acid for another at a position that is conserved across mammal species, though it is not conserved in lower species. Mutations in a nearby codon (Glu462Ala, Glu462Lys) have been reported in association with LQTS, supporting the functional importance of this region of the protein. In addition, Arg458His was not observed with a significant allele frequency in individuals of European ancestry as reported by the NHLBI ESP Exome Variant Server. In summary, with the clinical and molecular information available at this time, we cannot determine if Arg458His is a disease-causing mutation or a rare benign variant. The variant is found in POSTMORTEM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001842898	SCV001348368	uncertain significance	Cardiac arrhythmia	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 458 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals from control cohorts, who were not selected for cardiomyopathies or other heart diseases (PMID: 23299917, 25904541). This variant has been identified in 2/247666 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	RCV000182970	SCV003450470	uncertain significance	not provided	2024-10-18	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 458 of the SCN5A protein (p.Arg458His). This variant is present in population databases (rs373692157, gnomAD 0.006%). 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: 201452). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001842898	SCV004816459	uncertain significance	Cardiac arrhythmia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 458 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals from control cohorts, who were not selected for cardiomyopathies or other heart diseases (PMID: 23299917, 25904541). This variant has been identified in 2/247666 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.