Submissions for variant NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)

dbSNP: rs199473055

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434418	SCV000518408	likely pathogenic	not provided	2024-05-24	criteria provided, single submitter	clinical testing	Reported in association with Brugada syndrome (BrS) in published literature (PMID: 30193851, 22739120, 20129283); 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: 23874304, 30662450, 30232268, 24136861, 23805106, 20129283, 22581653, 26907222, 22871588, 22739120, 30476647, 32815768, 33131149, 34122134, 35305865, 30193851, 30203441, 23321620, 11960580)
Ambry Genetics	RCV000617193	SCV000738139	pathogenic	Cardiovascular phenotype	2020-09-22	criteria provided, single submitter	clinical testing	The p.R104W variant (also known as c.310C>T), located in coding exon 2 of the SCN5A gene, results from a C to T substitution at nucleotide position 310. The arginine at codon 104 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in individuals with Brugada syndrome, and was suggested to affect channel function by in vitro studies (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Clatot J et al. Cardiovasc. Res., 2012 Oct;96:53-63). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, internal structural analysis has predicted a disruptive effect of this alteration (Wu J. Science. 2015 Dec;350(6267):aad2395). In addition, an alteration affecting the same amino acid, R104Q, has also been described in association with Brugada syndrome and was shown to attenuate channel activities by in vitro assays (Levy-Nissenbaum E et al. Genet. Test., 2001;5:331-4; Gütter C et al. Front Physiol, 2013 Jun;4:153). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000434418	SCV002292504	pathogenic	not provided	2024-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the SCN5A protein (p.Arg104Trp). This variant is present in population databases (rs199473055, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 22739120, 30193851). ClinVar contains an entry for this variant (Variation ID: 67778). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22739120, 34122134). This variant disrupts the p.Arg104 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11960580, 19716085, 20129283, 23321620, 24136861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490655	SCV002800405	likely 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	2021-07-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003227634	SCV003925662	pathogenic	Brugada syndrome 1	2023-04-19	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM5, PM2_SUP
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317072	SCV004020423	pathogenic	Brugada syndrome (shorter-than-normal QT interval)	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.310C>T (p.Arg104Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249552 control chromosomes. c.310C>T has been reported in the literature in individuals affected with Brugada Syndrome (example, Kapplinger_2010, Clatot_2012, Berthome_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report reproducible experimental evidence evaluating an impact on protein function (example, Clatot_2012, Doisne_2021). The most pronounced variant effect results in abolished sodium current in-vitro and a dominant-negative effect on wild-type channel assembly that was reproducible in a murine model. The following publications have been ascertained in the context of this evaluation (PMID: 30193851, 22739120, 34122134, 20129283). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786341	SCV005400264	pathogenic	Sick sinus syndrome 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss of function or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene have autosomal dominant inheritance. SSS is usually caused by biallelic variants; however, heterozygotes may show symptoms (OMIM, PMID: 30364184). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301690). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg104Gln) has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar. Another comparable variant, p.(Arg104Gly), has been classified as a VUS by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed in individuals with Brugada syndrome or other cardiac conditions (PMIDs: 20129283, 22739120, 31696929). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to abolish sodium channel conduction and significantly reduce protein levels in HEK293 cells. Variant protein was also shown to be retained in the ER in rat neonatal cardiomyocytes (PMID: 22739120). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058549	SCV000090069	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283;PMID:22739120). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.