Submissions for variant NM_000335.5(SCN5A):c.1943C>T (p.Pro648Leu)

gnomAD frequency: 0.00019  dbSNP: rs45609733

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041607	SCV000065303	uncertain significance	not specified	2017-03-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000225740	SCV000235393	uncertain significance	not provided	2024-05-03	criteria provided, single submitter	clinical testing	Published in vitro functional studies using whole-cell voltage clamp analysis suggest faster sodium channel inactivation compared to wild type, however, in vivo effect is unknown (PMID: 24613995); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15840476, 29728395, 32048431, 20129283, 19412328, 25898860, 28600387, 28807990, 26633542, 28150151, 19841300, 25904541, 22337857, 29884292, 22581653, 23631430, 26941339, 30193851, 32091595, 31737537, 34426522, 33131149, 30079003, 30203441, 24613995, 37937776)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225740	SCV000637094	uncertain significance	not provided	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 648 of the SCN5A protein (p.Pro648Leu). This variant is present in population databases (rs45609733, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 15840476, 19412328, 19841300, 20129283, 24613995, 26633542, 28600387, 30193851, 31737537). ClinVar contains an entry for this variant (Variation ID: 48292). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24613995, 32091595, 33131149). 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.
Ambry Genetics	RCV000620269	SCV000736463	uncertain significance	Cardiovascular phenotype	2019-10-14	criteria provided, single submitter	clinical testing	The c.1943C>T (p.P648L) alteration is located in exon 13 (coding exon 12) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1943, causing the proline (P) at amino acid position 648 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678931	SCV000805143	uncertain significance	Long QT syndrome 3	2018-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841596	SCV000904494	uncertain significance	Cardiac arrhythmia	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 648 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant may alter sodium channel inactivation kinetics but the change did not appear to be significant (PMID: 24613995). This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with familial dilated cardiomyopathy (PMID: 19412328), in individuals affected with unexplained cardiac arrest (PMID: 28600387, 32091595), and in an individual with irritable bowel syndrome, sinus bradycardia and heart block (PMID: 24613995). This variant has been identified in 14/279340 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041607	SCV000920192	uncertain significance	not specified	2024-09-18	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1943C>T (p.Pro648Leu) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251220 control chromosomes (gnomAD and publications). This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Arrhythmia (4e-05 vs 0.0001), allowing no conclusion about variant significance. c.1943C>T has been reported in the literature in individuals affected with varying cardiac phenotypes, including DCM (e.g. Hershberger_2008), LQTS (e.g. Kapa_2009, Lieve_2013), Brugada Syndrome (e.g. Kapplinger_2010, Pearman_2020), and SUDS/SIDS (e.g. Dewar_2017, Mellor_2017) without strong evdence for causality such as co-segregation studies. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (MYH7 c.2389G>A, p.Ala797Thr; MYH7 c.1357C>T, p.Arg453Cys; KCNH2 c.1139delT, p.Leu380fsX54). A functional study, Beyder_2014, found slower inactivation of whole-cell Na+ voltage-dependent current by mutant protein in comparison to the wild type, although the residual activity was at approximately 70% of wild-type levels, therefore the correlation of this finding to the established pathophysiology and mechanism of disease is uncertain. The following publications have been ascertained in the context of this evaluation (PMID: 24613995, 30143662, 28807990, 32091595, 19412328, 19841300, 20129283, 29728395, 23631430, 28600387, 33131149, 26633542, 31032819, 15840476, 25585270). ClinVar contains an entry for this variant (Variation ID: 48292). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000225740	SCV001153874	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253643	SCV001429477	uncertain significance	Brugada syndrome 1	2018-07-04	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000041607	SCV002073479	uncertain significance	not specified	2022-01-18	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of proline with leucine at codon 648 of the SCN5A gene. The variant has an entry in ClinVar (48292) NM_000335.5 (SCN5A): c.1943C>T (p.Pro648Leu) and has occurred in GnomAD with a total MAF of 0.0045% and highest MAF of 0.0090% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated. An in vitro functional study suggests that this variant may impact sodium channel function (PMID: 24613995). The variant has previously been reported in patients referred for long QT syndrome and Brugada syndrome testing (PMID: 20129283, 15840476, 19841300), a patient affected with dilated cardiomyopathy (PMID: 19412328), and a patient that survived an unexplained cardiac arrest (PMID: 28600387). Further evidence is needed to establish whether this variant contributes to disease formation. The variant has therefore been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002477133	SCV002785412	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	2021-09-22	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058466	SCV000089986	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19841300). 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	RCV000417360	SCV000503525	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.
GenomeConnect - Brain Gene Registry	RCV003987337	SCV004804553	not provided	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 12-29-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.