ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1820G>T (p.Gly607Val) (rs757119370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252061 SCV000318808 uncertain significance Cardiovascular phenotype 2013-07-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000182985 SCV000235385 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The G607V variant has not been published as pathogenic or been reported as benign to our knowledge. However, it has been observed both independently, and in conjunction with additional cardiogenetic variants, in other individuals referred for arrhythmia genetic testing at GeneDx, although segregation data are limited and not sufficient to further clarify the role of this variant in disease. Additionally, the G607V variant has also been observed in 11/99992 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Furthermore, G607V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000559640 SCV000637088 uncertain significance Brugada syndrome 2017-09-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 607 of the SCN5A protein (p.Gly607Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs757119370, ExAC 0.009%) but has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201461). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant identified in the SCN5A gene is located in the interdomain linker DI/DII region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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