Submissions for variant NM_000335.5(SCN5A):c.3875T>C (p.Phe1292Ser)

gnomAD frequency: 0.00048  dbSNP: rs41311127

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171772	SCV000055220	likely benign	Brugada syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151781	SCV000200232	uncertain significance	not specified	2014-07-23	criteria provided, single submitter	clinical testing	The Phe1293Ser variant in SCN5A has been reported in 2 individuals with Brugada syndrome (Priori 2002, Sommariva 2012), one of whom carried a frameshift variant in the other copy of SCN5A, but has also been identified in 1/590 Caucasian con trol chromosomes (Ackerman 2004) and in 4/8412 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/; dbSNP rs41311 127). This variant has also been identified by our laboratory in 1 Caucasian ind ividual with DCM, who had a pathogenic variant in a different gene. The affected amino acid is poorly conserved in evolution, raising the possibility that a cha nge at this position would be tolerated. Other computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Phe1293Ser variant is uncertain.
Invitae	RCV000058610	SCV000545025	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000058610	SCV000700035	likely benign	not provided	2017-05-30	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.3878T>C (p.Phe1293Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 49/119844 control chromosomes including ExAC at a frequency of 0.0004089, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667), suggesting this variant is likely a benign polymorphism. This variant has been reported in two Brugada syndrome (BrS) patients and one patient presenting with sodium channelopathy (cardiac symptoms, positive family history, and/or abnormal electrocardiogram) in literature (Priori_2002, Chockalingam_2012, and Sommariva_2013). In one BrS patient, another truncating variant c.3258-3261del4 (p.E1087PfsX57) was also present (Sommariva_2013), supporting benign outcome. It has been also reported as polymorphism from published sources (Kapa_2009, Kapplinger_2010) as it was found in healthy controls of European origin. In ClinVar while two clinical labs have classified this variant as VUS, one lab has classified as likely benign. Taken together, this variant is currently classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001842352	SCV000904417	likely benign	Cardiac arrhythmia	2019-12-17	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845318	SCV000987360	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000058610	SCV001145505	likely benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147537	SCV001308366	uncertain significance	Brugada syndrome 1	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000058610	SCV001500310	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SCN5A: BS2
GeneDx	RCV000058610	SCV001863841	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33083721, 30847666, 29167113, 27153395, 11901046, 22885917, 15851227, 20129283, 23414114)
Ambry Genetics	RCV002354250	SCV002620547	likely benign	Cardiovascular phenotype	2018-03-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224134	SCV003920441	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	2021-03-30	criteria provided, single submitter	clinical testing	SCN5A NM_198056.3 exon 22 p.Phe1293Ser (c.3878T>C): This variant has been reported in the literature in at least two individuals with Brugada syndrome, one of whom also carried a truncating variant in SCN5A (Priori 2002 PMID:11901046, Sommariva 2012). However, this variant is present in 0.9% (93/10336) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-38603991-A-G) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:67833). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058610	SCV000090130	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:11901046;PMID:15851227;PMID:19841300;PMID:20129283).
CSER _CC_NCGL, University of Washington	RCV000417329	SCV000503533	uncertain significance	Long QT syndrome	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of Long QT syndrome.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000058610	SCV000924950	uncertain significance	not provided	2017-01-17	no assertion criteria provided	provider interpretation