Submissions for variant NM_000335.5(SCN5A):c.5869C>T (p.Arg1957Ter)

gnomAD frequency: 0.00004  dbSNP: rs757532106

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183137	SCV000235550	uncertain significance	not provided	2022-04-19	criteria provided, single submitter	clinical testing	Reported in association with LQTS, borderline QTc intervals, idopathic arrhythmia, and DCM (Trolle et al., 2013; Chang et al., 2014; Walsh et al., 2017; Mellor et al., 2017); Nonsense variant predicted to result in protein truncation as the last 59 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 15840476, 27532257, 24388587, 19862833, 28600387, 33087929, 32533946, 31447099, 23936059)
Eurofins Ntd Llc (ga)	RCV000183137	SCV000341424	uncertain significance	not provided	2018-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183137	SCV000829833	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1958*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs757532106, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome, dilated cardiomyopathy or unexplained cardiac arrest (PMID: 15840476, 19862833, 24388587, 27532257, 28600387, 29961767, 37652022). This variant is also known as c.5869C>T (p.Arg1957*) . ClinVar contains an entry for this variant (Variation ID: 201546). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect SCN5A function (PMID: 32533946). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg2012His) have been observed in individuals with SCN5A-related conditions (PMID: 27287068). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763107	SCV000893649	pathogenic	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	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842930	SCV001351106	uncertain significance	Cardiac arrhythmia	2022-12-16	criteria provided, single submitter	clinical testing	This c.5872C>T (p.Arg1958*) variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal. This variant is also described as c.5869C>T (p.Arg1957*) based on a different transcript NM_000335.5. This variant occurs in the last exon and is expected to result in a truncated protein product missing the last 59 amino acids of the protein. To our knowledge, functional studies have not been reported for this variant. However, a different truncation variant p.Arg1944* missing the last 73 amino acids of the protein has shown negligible effects on protein expression and function in an experimental study (PMID: 28370132) (ClinVar variation ID: 201596). This c.5872C>T (p.Arg1958*) variant has been reported in an individual affected with long QT syndrome (PMID: 19862833), in two individuals having borderline long QTc intervals (PMID: 23936059, 24388587), in two individuals with dilated cardiomyopathy (PMID: 27532257, 29961767) and in an individual with unexplained cardiac arrest (PMID: 28600387). This variant has also been identified in 13/276598 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000183137	SCV002502763	likely pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354483	SCV002652791	uncertain significance	Cardiovascular phenotype	2023-03-02	criteria provided, single submitter	clinical testing	The p.R1958* variant (also known as c.5872C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5872. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration has been reported in a long QT syndrome cohort, a dilated cardiomyopathy cohort, a Turner syndrome cohort, a hearing loss cohort, and a cardiac arrest survivor cohort (Hedley PL et al. Hum. Mutat. 2009;30:1486-511; Trolle C et al. PLoS ONE. 2013;8:e69614; Chang RK et al. J. Pediatr. 2014;164:590-5.e1-3; Mellor G et al. Circ Cardiovasc Genet. 2017;10:e001686; Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has also been reported in biobank cohorts (Zouk et al. Am J Hum Genet, 2019 Sep;105:588-605; Van Hout CV et al. Nature, 2020 Oct;586:749-756). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of SCN5A, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 59 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.