Submissions for variant NM_000335.5(SCN5A):c.1990A>G (p.Ser664Gly)

gnomAD frequency: 0.00001  dbSNP: rs757444820

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523591	SCV000617044	uncertain significance	not provided	2016-08-29	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN5A gene. The S664G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in one other unrelated individual referred for LQTS genetic testing at GeneDx. S664G was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The S664G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position in the cytoplasmic linker between DI and DII of the protein that is conserved across species. Biochemical analysis of Nav1.5 protein (encoded by the SCN5A gene) isolated from adult mouse ventricular cardiomyocytes showed that the S664 residue is phosphorylated in situ; however, the functional significance of this phosphorylation remains to be elucidated (Marionneau et al., 2012). Although missense variants in nearby residues (A662S, A665S) have been reported in the Human Gene Mutation Database in association with sudden unexplained death and LQTS (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the S664G variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Color Diagnostics, LLC DBA Color Health	RCV001841410	SCV001359802	uncertain significance	Cardiac arrhythmia	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 2/249028 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	RCV000523591	SCV001508318	uncertain significance	not provided	2024-10-22	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 664 of the SCN5A protein (p.Ser664Gly). This variant is present in population databases (rs757444820, gnomAD 0.002%). 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: 449199). 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.
All of Us Research Program, National Institutes of Health	RCV001841410	SCV004828354	uncertain significance	Cardiac arrhythmia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 2/249028 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.
Ambry Genetics	RCV004023536	SCV005031238	uncertain significance	Cardiovascular phenotype	2023-11-03	criteria provided, single submitter	clinical testing	The p.S664G variant (also known as c.1990A>G), located in coding exon 12 of the SCN5A gene, results from an A to G substitution at nucleotide position 1990. The serine at codon 664 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.