ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4823C>T (p.Ser1608Leu)

gnomAD frequency: 0.00001  dbSNP: rs199473622
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001842729 SCV001342862 uncertain significance Cardiac arrhythmia 2021-08-09 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 1609 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 infant affected with sudden death (PMID: 25757662). This variant has been identified in 3/250002 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.
Invitae RCV001566400 SCV001396350 uncertain significance not provided 2023-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1609 of the SCN5A protein (p.Ser1609Leu). This variant is present in population databases (rs199473622, gnomAD 0.003%). This missense change has been observed in individual(s) with sudden unexpected death in infancy (PMID: 25757662). ClinVar contains an entry for this variant (Variation ID: 919932). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 25757662). 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.
GeneDx RCV001566400 SCV001789911 uncertain significance not provided 2020-10-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25757662, 31043699)
Ambry Genetics RCV002339446 SCV002635064 uncertain significance Cardiovascular phenotype 2020-07-30 criteria provided, single submitter clinical testing The p.S1609L variant (also known as c.4826C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4826. The serine at codon 1609 is replaced by leucine, an amino acid with dissimilar properties, and is located in the transmembrane DIV-S3 domain. This variant was reported in a sudden infant death cohort, but clinical details were not provided; limited functional studies suggested possible electrophysiological effects but the clinical impact is uncertain (Winkel BG et al. Heart Rhythm, 2015 Jun;12:1241-9). This amino acid position is not well 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.

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