ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1943C>T (p.Pro648Leu) (rs45609733)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620269 SCV000736463 uncertain significance Cardiovascular phenotype 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center 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.
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.
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 RCV000771798 SCV000904494 uncertain significance Arrhythmia 2018-10-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the interdomain linker between transmembrane domains DI and DII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental 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 referred for long QT syndrome and Brugada syndrome genetic testing (PMID: 15840476, 20129283), and in an irritable bowel syndrome patient with sinus bradycardia and heart block (PMID: 24613995). This variant has also been identified in 14/276028 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000225740 SCV000235393 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The P648L variant has been reported in association with multiple phenotypes including LQTS, DCM, Brugada syndrome, sudden unexplained death and cardiac arrest (Tester et al., 2005; Hershberger et al., 2008; Kapplinger et al., 2010; Dewar et al., 2017; Mellor et al., 2017). The P648L variant is observed in 14/276028 (0.0051%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the P648L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In a study examining the role of SCN5A pathogenic variants in irritable bowel syndrome, whole-cell voltage clamp analysis demonstrated that P648L results in faster sodium channel inactivation (Beyder et al., 2014), though it is not clear how well this study reproduces in vivo conditions. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America 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."
Invitae RCV000560041 SCV000637094 uncertain significance Brugada syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 648 of the SCN5A protein (p.Pro648Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs45609733, ExAC 0.01%). This variant has been reported in individuals affected with long QT syndrome (PMID: 19841300), dilated cardiomyopathy (PMID: 19412328), sinus bradycardia and heart block (PMID: 24613995), and in individuals referred for long QT syndrome and Brugada genetic testing (PMID: 15840476, 20129283) and sudden unexplained cardiac arrest (PMID: 28600387). ClinVar contains an entry for this variant (Variation ID: 48292). Experimental studies have shown that this missense change does not significantly alter SCN5A activity (PMID: 24613995). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.