ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3521G>A (p.Arg1174His)

gnomAD frequency: 0.00005  dbSNP: rs374314562
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001591080 SCV000545104 uncertain significance not provided 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1175 of the SCN5A protein (p.Arg1175His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 406448). 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 RCV001841362 SCV000905130 uncertain significance Cardiac arrhythmia 2023-03-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1175 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/229824 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.
GeneDx RCV001591080 SCV001815267 uncertain significance not provided 2022-04-08 criteria provided, single submitter clinical testing Identified in 1/8975 control individuals assembled from a combination of in-house controls and data from the 1000 Genomes Project and the NHLBI Exome Sequencing Project (Kapplinger et al., 2015); 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: 25904541)
Ambry Genetics RCV002451094 SCV002613418 uncertain significance Cardiovascular phenotype 2020-12-07 criteria provided, single submitter clinical testing The p.R1175H variant (also known as c.3524G>A), located in coding exon 19 of the SCN5A gene, results from a G to A substitution at nucleotide position 3524. The arginine at codon 1175 is replaced by histidine, an amino acid with highly similar properties, and is located in the DII/DIII region of the protein. This alteration was reported in one ostensibly healthy individual (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other 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 RCV002481401 SCV002780987 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 2021-09-18 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001841362 SCV004820430 uncertain significance Cardiac arrhythmia 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1175 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/229824 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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