ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.665G>A (p.Arg222Gln) (rs45546039)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182941 SCV000235337 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R222Q pathogenic variant in the SCN5A gene has been reported in association with LQTS, DCM, and multifocal ectopic Purkinje-related premature contractions (MEPPC) (Hershberger et al., 2008; Kapplinger et al., 2009; Morales et al., 2010; Cheng et al., 2010; McNair et al., 2011; Laurent et al., 2012; Walsh et al., 2017). In addition, R222Q has been reported to segregate with disease in several unrelated families with DCM and/or arrhythmia (Hershberger et al., 2008; Morales et al., 2010; Cheng et al., 2010; McNair et al., 2011; Laurent et al., 2012). Furthermore, R222Q is not observed in large population cohorts (Lek et al., 2016). The R222Q variant is a semi-conservative amino acid substitution that is located in the S4 transmembrane voltage sensor of Domain I in the Nav1.5 channel. In-silico analyses, including protein predictors and evolutionary conservation, also support a deleterious effect. Moreover, several functional studies show that the R222Q variant results in abnormal sodium channel current (Cheng et al., 2010; Laurent et al., 2012; Mann et al., 2012; Nair et el., 2012).
Invitae RCV000464847 SCV000545097 pathogenic Brugada syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 222 of the SCN5A protein (p.Arg222Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with dilated cardiomyopathy, arrhythmias and long QT syndrome and segregates with disease in many families (PMID: 19716085, 21483645, 22766342, 22999724, 25210054). ClinVar contains an entry for this variant (Variation ID: 39444). Experimental studies have shown that this missense change causes a net gain of function in the channel due to proton leakage (PMID: 22710484, 24815523, 25624448). This variant is located in domain I of the voltage-sensing transmembrane segment S4 of SCN5A where similar pathogenic variants have been reported (PMID: 15671429, 24815523, 25741286). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678965 SCV000805181 pathogenic Long QT syndrome 3 2018-05-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763109 SCV000893651 pathogenic Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000182941 SCV000928005 pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing
OMIM RCV000032639 SCV000056402 pathogenic Dilated cardiomyopathy 1E 2012-10-16 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211852 SCV000065333 pathogenic Primary dilated cardiomyopathy 2013-03-06 no assertion criteria provided clinical testing The Arg222Gln variant in SCN5A has been reported in at least 8 families with DCM , LQTS and/or arrhythmias and segregated with disease in at least 38 relatives a cross (Hershberger 2008, Kapplinger 2009, Morales 2010, Mann 2012, Laurent 2012, Nair 2012, McNair 2012). Electrophysiological studies have shown that the Arg22 2Gln variant impacts protein function (Mann 2012, Laurent 2012, Nair 2012, Cheng 2012). This variant has not been identified in large and broad European America n and African American populations by the NHLBI Exome Sequencing Project (http:/ /; dbSNP rs45546039), which is consistent with a pathog enic role. In summary, this variant meets our criteria to be classified as patho genic ( based upon segregation studies and absence from controls.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058833 SCV000090353 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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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