Submissions for variant NM_000335.5(SCN5A):c.2548G>A (p.Val850Met)

gnomAD frequency: 0.00001  dbSNP: rs911293694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841025	SCV001354987	uncertain significance	Cardiac arrhythmia	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 850 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 an individual affected with Brugada syndrome (PMID: 32268277), in two related individuals affected with inherited arrhythmia syndromes (Mizusawa 2016, dissertation, University of Amsterdam), and in another individual suspected of having cardiovascular disease (PMID: 31696929). This variant has been identified in 2/251416 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262686	SCV001440640	uncertain significance	Brugada syndrome 1	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001341719	SCV001535605	uncertain significance	Brugada syndrome	2022-09-27	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 850 of the SCN5A protein (p.Val850Met). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 925869). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223280	SCV002501643	uncertain significance	not provided	2021-07-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429831	SCV002742921	uncertain significance	Cardiovascular phenotype	2021-11-02	criteria provided, single submitter	clinical testing	The p.V850M variant (also known as c.2548G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2548. The valine at codon 850 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in a Brugada syndrome case and in an arrhythmia cohort; however, clinical details were limited for both (Li X et al. Ann Hum Genet, 2020 03;84:161-168; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.