ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.569G>A (p.Arg190Gln) (rs199473069)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182933 SCV000235328 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing The R190Q variant of uncertain significance in the SCN5A gene has been reported in a patient suspected to have Brugada syndrome, as well as several patients suspected of having long QT syndrome (Chung et al., 2007; Ogowa et al., 2010; Reithmann et al., 2012; Anderson et al., 2017). However, LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants. As this variant has been identified in individuals evaluated for diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain. Furthermore, functional studies do not demonstrate a deleterious effect (Kapplinger et al., 2015; Anderson et al., 2017). The R190Q variant is observed 12/270132 (0.004%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the R190Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color RCV000777723 SCV000913669 uncertain significance Arrhythmia 2019-07-27 criteria provided, single submitter clinical testing
Invitae RCV000824478 SCV000965377 uncertain significance Brugada syndrome 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 190 of the SCN5A protein (p.Arg190Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199473069, ExAC 0.1%). This variant has been observed in several individuals affected with long QT (LQT) syndrome, prolonged QT, or Brugada syndrome (PMID: 17905336, 21908450, 28412158, 20137763). ClinVar contains an entry for this variant (Variation ID: 68005). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000987238 SCV001136488 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058799 SCV000090319 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:17905336). 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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