Submissions for variant NM_000335.5(SCN5A):c.2859C>G (p.Asp953Glu)

gnomAD frequency: 0.00001  dbSNP: rs762818132

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183014	SCV000235421	uncertain significance	not provided	2014-04-08	criteria provided, single submitter	clinical testing	p.Asp953Glu (GAC>GAG): c.2859 C>G in exon 17 of the SCN5A gene (NM_198056.2) The D953E variant has not been published as a mutation or as a benign polymorphism to our knowledge. The D953E variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. A missense mutation in nearby residues (Q960K) has been reported in association with LQTS, supporting the functional importance of this region of the protein. However, the D953E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183014	SCV000760265	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 953 of the SCN5A protein (p.Asp953Glu). 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 201482). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs762818132, gnomAD 0.002%).
Ambry Genetics	RCV002433808	SCV002749923	uncertain significance	Cardiovascular phenotype	2021-07-26	criteria provided, single submitter	clinical testing	The p.D953E variant (also known as c.2859C>G), located in coding exon 16 of the SCN5A gene, results from a C to G substitution at nucleotide position 2859. The aspartic acid at codon 953 is replaced by glutamic acid, an amino acid with highly similar properties, and is located in the interdomain linker DII/DIII region. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003591707	SCV004361678	uncertain significance	Cardiac arrhythmia	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 953 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248594 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.
All of Us Research Program, National Institutes of Health	RCV003591707	SCV004819787	uncertain significance	Cardiac arrhythmia	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 953 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248594 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.