ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2398C>T (p.Arg800Cys)

gnomAD frequency: 0.00001  dbSNP: rs764252430
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521255 SCV000617057 uncertain significance not provided 2022-12-06 criteria provided, single submitter clinical testing Reported in an individual with HCM who also harbored a variant in the MYH7 gene, and the MYH7 variant segregated with HCM in another family member; however, segregation analysis was not definitive (Dias et al., 2021); 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: 34555931)
Invitae RCV000521255 SCV000830795 uncertain significance not provided 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 800 of the SCN5A protein (p.Arg800Cys). This variant is present in population databases (rs764252430, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 35124229). ClinVar contains an entry for this variant (Variation ID: 449205). 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 RCV001841411 SCV001358005 uncertain significance Cardiac arrhythmia 2023-01-20 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 800 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 performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (Schymanski 2017, dissertation, The Ohio State University) and in another individual affected with hypertrophic cardiomyopathy (PMID: 34555931). This variant has also been reported in an individual from a cohort of participants undergoing whole exome sequencing in clinical research studies (PMID: 30122538). This variant has been identified in 3/280184 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 RCV002481694 SCV002781428 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 2021-08-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV003302753 SCV004007602 uncertain significance Cardiovascular phenotype 2023-06-09 criteria provided, single submitter clinical testing The p.R800C variant (also known as c.2398C>T), located in coding exon 14 of the SCN5A gene, results from a C to T substitution at nucleotide position 2398. The arginine at codon 800 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a cardiovascular genetic testing cohort and a Brugada syndrome cohort; however, clinical details were limited in both cases (VanDyke RE et al. J Genet Couns, 2021 Apr;30:503-512; Pannone L et al. Europace, 2023 May;25:[ePub ahead of print]). 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.
All of Us Research Program, National Institutes of Health RCV001841411 SCV004815737 uncertain significance Cardiac arrhythmia 2023-08-28 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 800 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 performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (Schymanski 2017, dissertation, The Ohio State University) and in another individual affected with hypertrophic cardiomyopathy (PMID: 34555931). This variant has also been reported in an individual from a cohort of participants undergoing whole exome sequencing in clinical research studies (PMID: 30122538). This variant has been identified in 3/280184 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.

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