ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.44G>C (p.Arg15Thr)

gnomAD frequency: 0.00003  dbSNP: rs373410109
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000151810 SCV000200277 uncertain significance not specified 2013-05-22 criteria provided, single submitter clinical testing The Arg15Thr variant in SCN5A has not been reported in individuals with cardiomy opathy, but has been identified in 1/8336 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This frequenc y is too low to rule out a role in disease. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. Additional informati on is needed to fully assess the clinical significance of the Arg15Thr variant.
Color Diagnostics, LLC DBA Color Health RCV001842478 SCV000914098 uncertain significance Cardiac arrhythmia 2022-12-06 criteria provided, single submitter clinical testing This missense variant replaces arginine with threonine at codon 15 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 long QT syndrome, in an individual suspected of having long QT syndrome, and in five asymptomatic family members (PMID: 29033053, 31737537). This variant has been identified in 11/279748 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 RCV003137650 SCV001376891 uncertain significance not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 15 of the SCN5A protein (p.Arg15Thr). This variant is present in population databases (rs373410109, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of long QT Syndrome (PMID: 31737537, 35703482; Invitae). ClinVar contains an entry for this variant (Variation ID: 165163). 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.
Ambry Genetics RCV002326869 SCV002635416 uncertain significance Cardiovascular phenotype 2022-05-10 criteria provided, single submitter clinical testing The p.R15T variant (also known as c.44G>C), located in coding exon 1 of the SCN5A gene, results from a G to C substitution at nucleotide position 44. The arginine at codon 15 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an arrhythmia cohort with limited clinical details, as well as in a control population and in unaffected family members in a family with long QT syndrome and an additional alteration in KCNQ1 identified (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Zafari Z et al. J Electrocardiol, 2017 Jul;50:912-918; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is not well 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.
Fulgent Genetics, Fulgent Genetics RCV002492562 SCV002794072 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 2021-09-13 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003137650 SCV003821342 uncertain significance not provided 2021-11-15 criteria provided, single submitter clinical testing
New York Genome Center RCV003335133 SCV004046516 uncertain significance Dilated cardiomyopathy 1E 2023-03-09 criteria provided, single submitter clinical testing The c.44G>C variant identified in SCN5A has previously been reported in an individual with Long QT Syndrome, but its pathogenicity remains uncertain [PMID: 31737537]. The variant has been deposited in ClinVar as a Variant of Uncertain Significance by multiple submitters [ClinVar ID: 165163]. The c.44G>C variant is observed in 21 alleles (~0.0036% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which may include individuals with cardiac disorders. The c.44G>C variant is located in exon 2 of this 28-exon gene and predicted to replace an evolutionarily conserved (in mammals) arginine amino acid with threonine at position 15(p.(Arg15Thr). In silico predictions are inconclusive of damaging effect of the p.(Arg15Thr) variant [CADD v1.6 = 21.1, REVEL = 0.611]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.44G>C p.(Arg15Thr) variant identified in SCN5A is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV001842478 SCV004824241 uncertain significance Cardiac arrhythmia 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces arginine with threonine at codon 15 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 long QT syndrome, in an individual suspected of having long QT syndrome, and in five asymptomatic family members (PMID: 29033053, 31737537). This variant has been identified in 11/279748 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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