Submissions for variant NM_000335.5(SCN5A):c.820G>A (p.Gly274Ser)

gnomAD frequency: 0.00001  dbSNP: rs794728852

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766781	SCV000235345	uncertain significance	not provided	2016-05-25	criteria provided, single submitter	clinical testing	The G274S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G274S 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. This substitution occurs at a highly conserved position in the S5 transmembrane helix in homologous domain 1, which lines the pore of the NaV1.5 channel. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Multiple missense variants in nearby residues (Q270K, N275K, L276P, L276Q, H278D, C280Y) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014). However, the full significance of these variants is unknown. In addition, this variant has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory based on the lack of published case reports and functional studies in the literature (ClinVar SCV000255235.1, Landrum et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000199539	SCV000255235	uncertain significance	Brugada syndrome	2022-06-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 274 of the SCN5A protein (p.Gly274Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 30193851). ClinVar contains an entry for this variant (Variation ID: 201445). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182948	SCV000540293	uncertain significance	not specified	2016-12-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals and is not present in ExAC. It has been classified in ClinVar with 2 stars as VUS by GeneDx and Invitae.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000199539	SCV004697493	likely pathogenic	Brugada syndrome	2024-01-15	criteria provided, single submitter	clinical testing	Variant was found in asymptomatic male patient (37 y.o., Caucasian) with spontaneous Brugada-pattern found on routine ECG-screening. Family history was unremarkable. This substitution affects transmembrane-pore region of Nav1.5 channel. Variant is absent in gnomAD Exomes, and registered in gnomAD Genomes (found in 1 female carrier) with MAF 0.00000657. ClinVar contains an entry for this allele (Variation ID: 201445). All pathogenicity scores support damaging effect on protein. Variant meets criteria PM1_Strong, PM2, PP3 ACMG(2015) and Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls(2021) criteria and was classified as Likely Pathogenic (Class IV of pathogenicity).