Submissions for variant NM_000335.5(SCN5A):c.5287G>T (p.Val1763Phe)

dbSNP: rs199473309

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000058762	SCV004015009	uncertain significance	Brugada syndrome	2023-01-05	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV005255564	SCV005908307	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Dilated cardiomyopathy 1E	2022-05-05	criteria provided, single submitter	clinical testing	The p.Val1764Phe variant in the SCN5A gene was previously identified in this individual’s relative. This variant has been previously reported in at least 1 individual with Brugada syndrome (Zumhagen 2009, Kapplinger 2010) and has been submitted to ClinVar (Variation ID: 67976, ncbi.nlm.nih.gov/clinvar/). The p.Val1764Phe variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in one of the ion transport protein domains of SCN5A and other variants near the p.Val1764Phe variant, including p.Val1763Met, have been reported to be disease-associated. In silico tools predict that the p.Val1764Phe variant is deleterious; however, these predictions have not been tested directly. Using ACMG guidelines, this variant was classified as a variant of uncertain significance (ACMG evidence codes used: PM1, PM2_supporting, PP3).
Color Diagnostics, LLC DBA Color Health	RCV005402849	SCV006064639	uncertain significance	Cardiac arrhythmia	2024-07-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 1764 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a. 1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Computational prediction suggests that this variant may have 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 been reported in at least one individual affected with Brugada syndrome (PMID: 19029124, 20129283). This variant has not been identified 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058762	SCV000090282	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19808440;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.