ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3344G>A (p.Arg1115Gln) (rs369678002)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041616 SCV000065312 likely benign not specified 2012-11-07 criteria provided, single submitter clinical testing Arg1116Gln in exon 18 of SCN5A: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals, including several primates, have a glutamine (Gln) at thi s position despite high nearby amino acid conservation. In addition, computation al analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of imp act to the protein. This variant was also identified in 3/4196 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //
GeneDx RCV000656974 SCV000235440 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The R1116Q variant has been reported in one case of intrauterine fetal demise (IUFD) (Crotti et al., 2013); however, this variant has been reported in a control population (Kapplinger et al., 2015). It has also been observed in conjunction with other cardiogenetic variants in other individuals referred for cardiac genetic testing at GeneDx but informative segregation data are not available. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, in vitro functional studies showed that R1116Q retained the same functional properties as the wild-type allele (Crotti et al., 2013). This variant is also observed in 10/22420 (0.05%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). Nevertheless, R1116Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000463784 SCV000545085 uncertain significance Brugada syndrome 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1116 of the SCN5A protein (p.Arg1116Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs369678002, ExAC 0.1%). This variant has been reported in the literature in an unexplained intrauterine fetal death (PMID: 23571586), as well as in three control individuals (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 48299). One experimental study has shown that this missense variant does not affect protein function in vitro (PMID: 23571586). 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.
Color Health, Inc RCV001181116 SCV001346202 likely benign Arrhythmia 2019-02-01 criteria provided, single submitter clinical testing

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