Submissions for variant NM_000335.5(SCN5A):c.4807G>A (p.Val1603Met)

gnomAD frequency: 0.00004  dbSNP: rs199473280

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842370	SCV001345513	uncertain significance	Cardiac arrhythmia	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1604 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 been reported in two individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 32893267), in an individual affected with dilated cardiomyopathy (PMID: 25616976), and in an individual suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 8/277724 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328334	SCV001519410	uncertain significance	not specified	2021-03-11	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.4810G>A (p.Val1604Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4810G>A has been reported in the literature in individuals affected with Brugada Syndrome and Dilated Cardiomyopathy without strong evidence for causality (e.g. Kapplinger_2010, Xiong_2015, Berthome_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541539	SCV002312168	uncertain significance	not provided	2024-12-22	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 1604 of the SCN5A protein (p.Val1604Met). This variant is present in population databases (rs199473280, gnomAD 0.01%). This missense change has been observed in individual(s) with atrial fibrillation, Brugada syndrome, and/or right branch bundle block (PMID: 20129283, 25616976, 30193851, 32893267). ClinVar contains an entry for this variant (Variation ID: 67926). 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	RCV001842370	SCV004827599	uncertain significance	Cardiac arrhythmia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1604 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 been reported in two individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 32893267), in an individual affected with dilated cardiomyopathy (PMID: 25616976), and in an individual suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 8/277724 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	RCV004019054	SCV004944525	uncertain significance	Cardiovascular phenotype	2022-04-11	criteria provided, single submitter	clinical testing	The c.4810G>A (p.V1604M) alteration is located in exon 27 (coding exon 26) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 4810, causing the valine (V) at amino acid position 1604 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058709	SCV000090229	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.