Submissions for variant NM_000335.5(SCN5A):c.4400T>C (p.Val1467Ala)

gnomAD frequency: 0.00001  dbSNP: rs794728883

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183074	SCV000235483	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	Has not been previously published in association with SCN5A-related disease to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31677787)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183074	SCV000545047	uncertain significance	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1468 of the SCN5A protein (p.Val1468Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 201514). 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.
Color Diagnostics, LLC DBA Color Health	RCV001842923	SCV001349904	uncertain significance	Cardiac arrhythmia	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 1468 of the SCN5A protein. 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 1/236906 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.
Fulgent Genetics, Fulgent Genetics	RCV002503713	SCV002816646	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165396	SCV003903818	uncertain significance	Cardiovascular phenotype	2023-02-06	criteria provided, single submitter	clinical testing	The p.V1468A variant (also known as c.4403T>C), located in coding exon 24 of the SCN5A gene, results from a T to C substitution at nucleotide position 4403. The valine at codon 1468 is replaced by alanine, 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.
All of Us Research Program, National Institutes of Health	RCV001842923	SCV004824316	uncertain significance	Cardiac arrhythmia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 1468 of the SCN5A protein. 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 1/236906 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.