Submissions for variant NM_000335.5(SCN5A):c.5690G>A (p.Arg1897His)

gnomAD frequency: 0.00001  dbSNP: rs370694515

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000234809	SCV000240229	pathogenic	Long QT syndrome 3	2014-01-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216249	SCV000272417	uncertain significance	not specified	2019-02-06	criteria provided, single submitter	clinical testing	The p.Arg1898His variant in SCN5A has been reported in one patient with DCM (Haas 2015) and in one patient with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Te Riele 2017) and also in 1 individual with left ventricular non compaction with segmental hypertrophy (LMM data). It is also present in ClinVar (ID 207974). It has been identified in 7/30602 South Asian chromosomes by the gnomAD. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1898His variant is uncertain.
Ambry Genetics	RCV000247589	SCV000320364	uncertain significance	Cardiovascular phenotype	2023-04-17	criteria provided, single submitter	clinical testing	The p.R1898H variant (also known as c.5693G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5693. The arginine at codon 1898 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a dilated cardiomyopathy cohort, in an individual with confirmed myocarditis, and an individual with features of arrhythmogenic right ventricular cardiomyopathy (Haas J et al. Eur. Heart J., 2015;36:1123-35a; Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111; Nelson McMillan K. Artif Organs. 2019;43(1):21-29). This variant (referred to as p.R1865H) co-occurred with a de novo KCNH2 variant in an individual with overlapped phenotypes of LQTS and sinoatrial node dysfunction, while two reportedly unaffected relatives also had this SCN5A variant (Yang Z et al. Ann Noninvasive Electrocardiol. 2022 Jan;27(1):e12889). This variant has also been detected in a self-reported healthy cohort; however, details were limited (Bajaj A et al. Hum Genomics. 2022 Aug;16(1):30). One study indicated this alteration may have an impact on sodium channel function (Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111). 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.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000466757	SCV000541075	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia		criteria provided, single submitter	research
GeneDx	RCV000767135	SCV000589399	uncertain significance	not provided	2019-10-17	criteria provided, single submitter	clinical testing	Identified in a patient with DCM and a patient with clinical features suggestive of ARVC in the published literature (Haas et al., 2015; Te Riele et al., 2017); Functional studies in patient derived cells suggest this variant leads to a reduction in both peak sodium current and channel clusters at intercalated discs (Te Riele et al., 2017). However, further functional studies are needed to clarify the role of this variant in human disease.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID 207974; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25904541, 31336969, 28069705, 25163546, 29845439, 30205876, 30302938)
Invitae	RCV000767135	SCV000936963	uncertain significance	not provided	2024-01-16	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 1898 of the SCN5A protein (p.Arg1898His). This variant is present in population databases (rs370694515, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and/or long QT Syndrome (PMID: 25163546, 28069705, 34755423, 36303204). This variant is also known as c.G5639A, p.R1880H. ClinVar contains an entry for this variant (Variation ID: 207974). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 28069705). This variant disrupts the p.Arg1898 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 26173111), which suggests that this may be a clinically significant amino acid residue. 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	RCV001842945	SCV001341934	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1898 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant reduces sodium current and may disrupt formation of a functional complex with cell adhesion molecules (PMID: 28069705). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 25163546), arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and flu myocarditis (PMID: 30084490). This variant has also been identified in 12/280694 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.