ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2254G>A (p.Gly752Arg) (rs199473153)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182999 SCV000235404 pathogenic not provided 2017-09-25 criteria provided, single submitter clinical testing The G752R pathogenic variant in the SCN5A gene has been reported in multiple unrelated individuals with Brugada syndrome (Smits et al., 2002; Potet et al., 2003; Probst et al., 2009; Kapplinger et al., 2010; Kapplinger et al., 2015; Le Scouarnec et al., 2015). Out of these individuals, G752R was found to segregate with disease in over ten individuals from two unrelated families (Potet et al., 2003; Probst et al., 2009). The G752R variant has also been described in one individual with DCM (Hoogendijk et al., 2010). Furthermore, G752R is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, G742R is a non-conservative amino acid substitution that occurs within the S1 helical transmembrane domain of repeat II at a position that is conserved across species. Moreover, functional studies indicate that G752R results in a loss of function of the sodium channel (Potet et al., 2003; Hoogendijk et al., 2010; Varga et al., 2015). In summary, G752R in the SCN5A gene is interpreted as a pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000058491 SCV000256656 likely pathogenic Brugada syndrome 2015-04-14 criteria provided, single submitter research The SCN5A Gly752Arg variant has been identified in several unrelated individuals with Brugada syndrome (Smits JP, et al., 2002, Meregalli PG, et al., 2009; Kapplinger JD, et al., 2010; Le Scouarnec S, et al., 2015) and was found to be absent in >1300 controls (Kapplinger, JD et al., 2010). The variant has also been reported to segregate with disease in families with Brugada syndrome (Potet F, et al., 2003; Probst V et al., 2009) with functional studies showing deleterious effects on mutant sodium channels (Potet F, et al., 2003). We identified SCN5A Gly752Arg in an Asian proband with Brugada Syndome. The proband had a cardiac arrest whilst febrile aged 2yrs and has a family history of SCD. The SCN5A Gly752Arg variant is found at a low frequency in the 1000 genomes project (MAF= 0.0004; http://www.1000genomes.org/) and is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. Based on the current literature, rarity in general populations and in silico tool predictions we have evaluated this variant as "likely pathogenic".
Ambry Genetics RCV000244833 SCV000320129 pathogenic Cardiovascular phenotype 2018-09-07 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
Invitae RCV000058491 SCV001220586 pathogenic Brugada syndrome 2019-04-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 752 of the SCN5A protein (p.Gly752Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Brugada syndrome in a family (PMID: 12693506) and has been observed in individuals affected with Brugada syndrome (PMID: 25904541, 20129283) and in an individual affected with dilated cardiomyopathy (PMID: 20022821). ClinVar contains an entry for this variant (Variation ID: 67723). This variant has been reported to affect SCN5A protein function (PMID: 12693506, 26283144, 20022821). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058491 SCV000090011 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12106943;PMID:12693506;PMID:19251209;PMID:20129283). 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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