ClinVar Miner

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

gnomAD frequency: 0.00019  dbSNP: rs45609733
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Total submissions: 14
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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 2023-04-06 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 (Beyder et al., 2014), however, in vivo effect is unknown; In silico analysis supports 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, 30203441, 33131149, 24613995)
Invitae RCV000225740 SCV000637094 uncertain significance not provided 2024-01-20 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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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 2018-05-08 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. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 279294 control chromosomes (gnomAD and publications). The observed variant frequency within African control individuals in the gnomAD database is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant could be a benign polymorphism found primarily in populations of African origin. The variant, c.1943C>T, has been reported in the literature in multiple affected individuals diagnosed with varying cardio phenotypes: DCM (Hershberger_2008), LQTS (Kapa_2009, Lieve_2013), Brugada (Kapplinger_2010), and SUDS/SIDS (Dewar_2017, Mellor_2017). Including individuals that have undergone multiple gene panels in which the variant of interest was the only indicated variant to be identified, although cosegregation data was not provided. Therefore, these data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance" (4x) and "likely pathogenic" (1x). 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/.

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