ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4015G>A (p.Val1339Ile) (rs199473605)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058628 SCV000090148 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19648062;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 RCV000183058 SCV000235467 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The V1340I variant has been reported in association with Brugada syndrome; however, this variant was also reported in multiple unaffected family members (Samani et al., 2009; Kapplinger et al., 2010; Garcia-Castro et al., 2010). This variant is observed in 13/277178 (0.005%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The V1340I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, functional studies suggest the presence of this variant may alter protein interactions under various experimental conditions (Samani et al., 2009); however, it is not known whether these findings are biological or clinically relevant in vivo. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000058628 SCV000259420 uncertain significance Brugada syndrome 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1340 of the SCN5A protein (p.Val1340Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199473605, ExAC 0.03%). This variant has been reported in the literature in several individuals affected with Brugada syndrome, including one individual that experienced symptoms during febrile illness (PMID: 20129283, 20609320, 19648062). It has also been reported in unaffected relatives of a Brugada patient (PMID: 20609320). These unaffected individuals had normal ECGs at baseline and following provocative testing using a sodium-channel blocker (PMID: 20609320). ClinVar contains an entry for this variant (Variation ID: 67849). Experimental studies have shown that this variant affects SCN5A channel function in vitro (PMID: 19648062). In summary, this is a rare variant that has been reported in affected individuals and has functional data suggestive of a deleterious effect. However, there is no segregation data and a pharmacological challenge in unaffected individuals carrying this variant did not generate a Brugada ECG. For these reasons, this variant has been classified as a Variant of Uncertain Significance.

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