Submissions for variant NM_000335.5(SCN5A):c.262A>G (p.Ser88Gly)

gnomAD frequency: 0.00001  dbSNP: rs779961972

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182922	SCV000235317	uncertain significance	not provided	2017-05-22	criteria provided, single submitter	clinical testing	p.Ser88Gly (S88G) AGC>GGC: c.262 A>G in exon 2 of the SCN5A gene (NM_198056.2) The S88G variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The S88G variant is a non-conservative amino acid substitution because these residues differ in polarity, charge, size and/or other properties and are more likely to impact secondary structure. Furthermore, the S88G variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in nearby residues (D84N, Y87C, F93S) have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. However, the S88 residue is not conserved across species and in silico analysis predicts S88G is probably benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if S88G is a disease-causing mutation or a rare benign variant. The variant is found in BRUGADA panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001842891	SCV001339376	uncertain significance	Cardiac arrhythmia	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 88 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 3/223034 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	RCV000182922	SCV003781747	uncertain significance	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 88 of the SCN5A protein (p.Ser88Gly). This variant is present in population databases (rs779961972, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448, 32880476). ClinVar contains an entry for this variant (Variation ID: 201429). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000182922	SCV004154194	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	SCN5A: PM2
All of Us Research Program, National Institutes of Health	RCV001842891	SCV004831481	uncertain significance	Cardiac arrhythmia	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 88 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 3/223034 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.