Submissions for variant NM_000335.5(SCN5A):c.659C>T (p.Thr220Ile)

gnomAD frequency: 0.00068  dbSNP: rs45620037

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151804	SCV000200270	likely benign	not specified	2015-01-02	criteria provided, single submitter	clinical testing	p.Thr220Ile in exon 6 of SCN5A: This variant has was initially believed to be di sease causing based on its detection 12 probands with a range of SCN5-related di sorders (CSD, DCM, LQTS) and absence from controls (Benson 2003, Olson 2005, Kap plinger 2010, Oleson 2012, Crottie 2013, GeneDx, pers. comm.) as well as some in vitro functional data (Benson 2003, Butters 2010, Gui 2010). However, the varia nt is unlikely disease causing on its own based on its frequency in the general population (detected in 0.7% (30/4290) of European (Finnish) chromosomes and 0.1 % (46/43544) European (Non-Finnish) chromosomes screened by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45620037). It remain s possible that the Thr220Ile variant represents a modifier or risk allele.
GeneDx	RCV000586618	SCV000235335	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Reported in multiple patients with several different clinical phenotypes, including cardiomyopathy, sick sinus syndrome (SSS), Brugada syndrome, Long QT syndrome (LQTS), intrauterine fetal demise (IUFD), sudden death, and complete heart block; however, several of these individuals also harbored a second variant in SCN5A or in another gene, and some individuals who harbored only the p.(T220I) variant were clinically unaffected (PMID: 14523039, 15671429, 20129283, 21273195, 23571586, 24136861, 26636822, 26884609, 24762805, 26743238, 29709244, 27332903, 27066507, 32048431, 20539757, 25351510, 31737537, 22677073); Published studies examined the functional effect of the p.(T220I) variant, with the general conclusion that this variant impairs sodium ion channel function (PMID: 20539757, 14523039, 20448214); however, it is unclear how these studies may translate to a pathogenic role in vivo; 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: 26636822, 24055113, 22685113, 20448214, 23414114, 24613995, 24784157, 25637381, 25171853, 20129283, 23571586, 21273195, 15671429, 24136861, 26884609, 28150151, 34426522, 30203441, 20539757, 14523039, 29709244, 27332903, 26743238, 32048431, 31737537, 24762805, 25351510, 22677073, 35197637, 31337358, 27066507, 20384651, 21596231, 22581653, 24059039)
Invitae	RCV000586618	SCV000253663	benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000151804	SCV000264201	likely benign	not specified	2015-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251727	SCV000318636	likely benign	Cardiovascular phenotype	2021-05-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151804	SCV000700043	likely benign	not specified	2024-01-30	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.659C>T (p.Thr220Ile) results in a non-conservative amino acid change located in the Ion-transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 250790 control chromosomes. The observed variant frequency is approximately 6.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant is benign. c.659C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiac phenotypes (e.g. Benson_2003, Olson_2005, Kapplinger_2010, Amin_2011, Olesen_2012, Baskar_2014, Celestino-Soper_2015, Ceyhan-Birsoy_2015, Marschall_2019, Raju_2019), but without strong evidence for causality. In several of the reports, the variant was identified in unaffected family members, indicating that the variant may not co-segregate with disease (e.g. Benson_2003, Baskar_2014). In addition, co-occurrences with other pathogenic/likely pathogenic variants have been reported [SCN5A c.3142_3153delins11 (Baskar_2014); SCN5A p.Arg1623X (Benson_2003); SCN5A c.3512-1G>C (internal sample)], providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function and indicate that the variant may alter the properties or functions of sodium channels to varying degrees in-vitro (e.g. Benson_2003, Butters_2010, Gui_2010). The following publications have been ascertained in the context of this evaluation (PMID: 15671429, 20129283, 14523039, 20539757, 20448214, 22677073, 21273195, 24055113, 23571586, 22685113, 25637381, 24784157, 24762805, 25171853, 26636822, 27066507, 24613995, 31737537, 31337358, 32048431). ClinVar contains an entry for this variant (Variation ID: 9396). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622951	SCV000740421	uncertain significance	Primary familial dilated cardiomyopathy	2017-04-21	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678935	SCV000805147	uncertain significance	Long QT syndrome 3	2018-02-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841241	SCV000913694	likely benign	Cardiac arrhythmia	2018-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001146372	SCV001307115	uncertain significance	SCN5A-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM	RCV000009998	SCV000030219	pathogenic	Sick sinus syndrome 1	2005-01-26	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058832	SCV000090352	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:14523039;PMID:15671429;PMID:20129283;PMID:20448214;PMID:20539757;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148857	SCV000190601	uncertain significance	AV junctional rhythm	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000151804	SCV000280482	uncertain significance	not specified	2012-03-12	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr220Ile (c.659 C>T) in the SCN5A gene (NM_198056.2) Given the abundance of case data, it seems likely that this variant contributes to disease in some fashion. What is challenging is determining whether it is sufficient on its own to cause disease or whether it is a modifer of some sort, given the presence of another variant in several reported cases and the presence of the variant in general population samples. Given this, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in one patient with sick sinus syndrome who was a compound heterozygote for this variant and a nonsense variant, one family with familial DCM, two patients with Brugada (one was a compound heterozygote for this variant and another missense variant), one patient with early-onset lone atrial fibrillation, two unrelated cases of pediatric onset atrial standstill (both cases were compound heterozygotes), one case of intrauterine death, one case of sudden unexplained death, and one case of irritable bowel syndrome. Using a candidate gene approach, Benson et al (2003) sequenced SCN5A in 10 patients with pediatric onset sick sinus syndrome from 7 families. Probands from three of the families were compound heterozygotes for two SCN5A variants (6 variants in total). One proband inherited p.Thr220Ile from his father and p.Arg1623Ter from his mother. His mother and two other maternal relatives who carry p.Arg1623Ter have first degree heart block. The two other maternal relatives also had prolonged QRS. His father was not available for study, however the paternal grandmother carried p.Thr220Ile and had a normal evaluation. Ancestry is not noted. The researchers are from various American academic medical centers. Olson et al (2005) observed the variant in one of 156 unrelated patients with DCM who underwent analysis of SCN5A. The patient had familial DCM (ischemic disease was ruled out) with atrial fibrillation and heart block. He never had documented ventricular tachycardia. The authors do not note if an arrhythmic phenotype preceded the cardiomyopathic phenotype. A first cousin had DCM, incomplete bundle branch block and also carried the variant. Ancestry is not noted. The patients were seen at Mayo in Minnesota or Latter Day Saints in Utah. The variant is reported in a compendium of SCN5A variants seen in individuals referred for Brugada syndrome genetic testing at various centers around the world (Kapplinger et al 2010). The authors note that patients were included if the physician who referred for genetic tesitng had made a possible or definite diagnosis of Brugada. Phenotype was not confirmed by the investigators so presumably some individuals included in the compendium do not in fact have Brugada syndrome. Two patients carried the variant. One patient was studied by the Brugada group and the other was studied by a Dutch group (likely same case reported by the Dutch group in Amin et al 2011). One patient also carried another SCN5A variant, p.Glu439Lys. He was diagnosed with Brugada at 26 years of age. Oleson et al (2012) observed the variant in 1 of 192 individuals with early onset lone atrial fibrillation. The patient had paroxysmal lone atrial fibrillation starting at 35 years of age. QTc was 422 ms, sodium blocking challenge (ex. Procainamide) was not done, and there was no family history of atrial fibrillation. Individual ancestry is not reported, but the subjects were recruited in Denmark. At the 2014 HRS meeting Baskar et al reported an 11yo girl with atrial standstill who was a compound heterozygote for this variant and a frameshift in SCN5A. The missense variant was inherited from her father and he had a normal cardiology evaluation. The authors suggest that p.Thr220Ile may be a modifier. Ancestry was not reported. At the Dutch clinical genetics society meeting in 2014 Lightman et al reported a family with atrial standstill and this variant. There were three affected children: a male who presented with recurrent syncope at 9 months of age, had SVT and complete heart block and died at 2 years of age; two females with recurrent syncope requiring a pacemaker. Exome sequencing revealed the girls were compound heterozygotes for a nonsense variant in SCN5A previously seen in Brugada syndrome and p.Thr220Ile. The mother carried the nonsense variant an had shortness of breath and atrial standstill (and subsequently received a pacemaker). The father declined work-up. Ancestry is not noted but the authors are from the UK. Ackerman's group investigated the role of the major long QT genes in intrauterine death. The variant was seen in one of 91 unexplained intrauterine deaths, a caucasian male at 20 weeks gestational age (Crotti et al 2013). They classified this as a variant of uncertain significance. Ackerman's group also reported the variant in one of 173 cases of unexplained sudden death (with negative autopsies) who underwent analysis of five long QT genes and RYR2 in their lab (Tester et al 2012). The patient was a Caucasian female who died at 19 years of age with no prior cardiac history or significant family history. Using a candidate gene approach, Beyder et al (2014) sequenced SCN5A in 584 individuals with irritable bowel syndrome and identified this variant in one person. Cardiac phenotype and ancestry were not provided. Subjects were recruited at Mayo and in Sweden, Italy and Greece. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.487). The threonine at codon 220 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.S216L (DCM, AF, LQTS), p.R219H (DCM), p.R222Q (DCM, LQTS, Brugada), p.R225Q (LQTS), p.R225W (LQTS, Brugada), p.A226V (Brugada), p.A226D (idiopathic VF), p.I230T (conduction system disease), p.I230V (Brugada). The variant is in the voltage-sensing transmembrane segment S4. In vitro studies suggested a loss of function in the sodium channel (Benson et al 2003, Gui et al 2010, Butters et al 2010). In total the variant has been seen in 5 of 7845 published controls and individuals from publicly available population datasets. Note that only a very small portion of those match the patient's Hispanic origins. The variant was reported online in 4 of 4204 Caucasian individuals and 0 of 2016 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of July 30th, 2014, included in Dorschner et al 2013 and Risgaard et al 2013). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It was also reported in 1/379 individuals in 1000 genomes. The variant was not observed in the following published control samples: 75 individuals (Benson et al 2003), 250 with normal echos and ECGs (Olson et al 2005), 1300 (Kapplinger et al 2010, Crotti et al 2013).
OMIM	RCV000258831	SCV000328552	pathogenic	Dilated cardiomyopathy 1E	2005-01-26	no assertion criteria provided	literature only