Submissions for variant NM_000335.5(SCN5A):c.5236G>A (p.Val1746Met)

gnomAD frequency: 0.00001  dbSNP: rs199473630

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183111	SCV000235521	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing	The V1747M variant of uncertain significance in the SCN5A gene has been reported previously in a Japanese individual diagnosed with LQTS; however, no detailed clinical information or segregation data were provided (Itoh et al., 2010). The V1747M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although missense variants in nearby residues (G1743E, A1746T, G1748D) have been reported in the Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. The V1747M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to valine (V) are tolerated across species, and methionine (M) is tolerated at this position in at least vertebrates. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics	RCV000621542	SCV000736418	uncertain significance	Cardiovascular phenotype	2017-06-19	criteria provided, single submitter	clinical testing	The c.5239G>A (p.V1747M) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 5239, causing the valine (V) at amino acid position 1747 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183111	SCV000760226	uncertain significance	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1747 of the SCN5A protein (p.Val1747Met). This variant is present in population databases (rs199473630, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 20541041, 37089884). ClinVar contains an entry for this variant (Variation ID: 67970). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842381	SCV001736311	uncertain significance	Cardiac arrhythmia	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1747 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 been reported in an individual with long QT syndrome (PMID: 20541041) and in an individual affected with Brugada syndrome and dilated cardiomyopathy (PMID: 28567303). This variant has been identified in 7/282612 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.
Phosphorus, Inc.	RCV001823715	SCV002073387	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	This missense variant results in a substitution of valine with methionine at codon 1747 of the SCN5A gene (transcript NM_001099404.1). This variant has been reported in ClinVar (67970) NM_000335.5 (SCN5A):c.5236G>A (p.Val1746Met) and occurred in GnomAD with a total MAF of 0.0024% and highest MAF of 0.0058% in the East Asian population. This position is conserved. In silico functional algorithms conflict, predicting it as tolerated (SIFT) and possibly damaging (PolyPhen), but no functional studies were performed to confirm these predictions. The variant has been observed in an individual with long QT syndrome (PMID: 20541041). In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842381	SCV004821006	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1747 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 been reported in an individual with long QT syndrome (PMID: 20541041) and in an individual affected with Brugada syndrome and dilated cardiomyopathy (PMID: 28567303). This variant has been identified in 7/282612 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058756	SCV000090276	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.