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

gnomAD frequency: 0.00001  dbSNP: rs45546039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182941	SCV000235337	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the p.(R222Q) variant results in abnormal sodium channel current (Cheng et al., 2010; Laurent et al., 2012; Mann et al., 2012; Nair et el., 2012; Daniel et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 25624448, 24815523, 22999724, 24136861, 19412328, 19716085, 21167004, 28779003, 22766342, 29506689, 31317183, 31125670, 31514951, 25741286, 29871609, 27535533, 33131149, 20458009, 22710484, 21596231)
Invitae	RCV000182941	SCV000545097	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 222 of the SCN5A protein (p.Arg222Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy, arrhythmias and long QT syndrome (PMID: 19716085, 21483645, 22766342, 22999724, 25210054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39444). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22710484, 24815523, 25624448). 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; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 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
Genetics and Molecular Pathology, SA Pathology	RCV000032639	SCV004175210	pathogenic	Dilated cardiomyopathy 1E	2021-11-09	criteria provided, single submitter	clinical testing	The SCN5A c.665G>A variant is a single nucleotide change in exon 6/28 of the SCN5A gene, which is predicted to change the amino acid arginine at position 222 in the protein, to glutamine. Well-established functional studies show this variant has a deleterious effect on the resultant protein, with gain of function of the sodium channel due to proton leakage reported (PMID#22710484, 24815523, 25624448) (PS3). The variant has been identified in >15 probands with a clinical presentation of (or similar to) Dilated Cardiomyopathy 1E/Arrhythmia. This represents a significant increase in the prevalence of the variant in affected individuals compared with the prevalence in control subjects (PS4). This variant has been reported to co-segregate with disease (>20 segregants over 4 families PMID#19716085. 22766342) (PP1_strong) and is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het) (PM2). The variant has been reported in dbSNP, is reported as Pathogenic (2 star) by other diagnostic laboratories (ClinVar Variation ID: 39444) and is reported in HGMD as disease causing with a dilated cardiomyopathy phenotype (CM087605). Computational predictions support a deleterious effect on the gene or gene product (PP3).
OMIM	RCV000032639	SCV000056402	pathogenic	Dilated cardiomyopathy 1E	2012-10-16	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham 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:/ /evs.gs.washington.edu/EVS; dbSNP rs45546039), which is consistent with a pathog enic role. In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) 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.