ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5123C>T (p.Thr1708Met) (rs199473297)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617525 SCV000737887 uncertain significance Cardiovascular phenotype 2017-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058742 SCV000090262 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17697823;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183101 SCV000235511 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing The T1709M variant in the SCN5A gene has been reported in three unrelated individuals with suspected or confirmed diagnoses of Brugada syndrome and it was absent from more than 2,600 control alleles (Yokokawa et al., 2007; Kapplinger et al., 2010). However, specific clinical, segregation or functional data was not provided. This variant has been identified independently and/or in conjunction with additional variants in individuals referred for genetic testing at GeneDx for arrhythmia; but, the information obtained from testing of these individuals is not sufficient, and additional family studies are essential for full interpretation. Nevertheless,this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1709M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000058742 SCV000937421 uncertain significance Brugada syndrome 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1709 of the SCN5A protein (p.Thr1709Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199473297, ExAC 0.001%). This variant has been observed in individuals with suspected or diagnosed Brugada syndrome (PMID: 17697823, 27676163, 20129283, 25460174). ClinVar contains an entry for this variant (Variation ID: 67957). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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