ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4296G>C (p.Gly1432=) (rs794728935)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183191 SCV000235609 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing A novel variant of uncertain significance has been identified in the SCN5A gene. The synonymous G1433G (c.4299 G>C) variant has not been published as pathogenic or been reported as benign to our knowledge. In addition, it is not reported in large population cohorts (Lek et al., 2016). This single nucleotide substitution occurs in the last position of exon 24 and is predicted to destroy the natural donor splice site for intron 24, which may result in abnormal gene splicing. Guanine (G) is conserved at this position across mammals. A different nucleotide substitution at this position (c.4299 G>A, G1433G) has been reported in one individual referred for Brugada syndrome testing; however, no patient-specific clinical data were provided (Kapplinger et al., 2010). However, in the absence of functional mRNA studies, the physiological consequence of the c.4299 G>C variant cannot be precisely determined, and this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000544994 SCV000637153 uncertain significance Brugada syndrome 2017-05-01 criteria provided, single submitter clinical testing This sequence change affects codon 1433 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant also falls at the last nucleotide of exon 24 of the SCN5A coding sequence, which is part of the consensus splice site for this exon This variant is not present in population databases (ExAC no frequency). ClinVar contains an entry for this variant (Variation ID: 201590). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare splice site change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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