ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.718G>A (p.Val240Met) (rs199473076)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182946 SCV000235343 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing The V240M variant in the SCN5A gene has been reported in one individual referred for LQTS genetic testing and in one individual referred for Brugada syndrome genetic testing, and was not observed in 2,600 control alleles. Clinical and segregation information was not provided (Kapplinger et al., 2009; Kapplinger et al., 2010). The V240M variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V240M variant is a conservative amino acid substitution at a position that is conserved across species. In vitro analysis showed that the V240M variant results in slower inactivation of sodium channels in cardiomyocytes, however some result parameters were not statistically significant (Fatima et al., 2013). Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000542318 SCV000637204 uncertain significance Brugada syndrome 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 240 of the SCN5A protein (p.Val240Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 24349418) and individuals with Brugada syndrome (PMID: 21273195). It has also been observed in individuals referred for arrhythmia genetic testing (PMID: 19716085, 20129283). ClinVar contains an entry for this variant (Variation ID: 68039). Experimental studies have shown that this missense change has a minor effect on current when examined in a pluripotent stem cell system, but the clinical significance of this is uncertain (PMID: 24349418). In summary, this variant has uncertain impact on SCN5A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000584760 SCV000692541 uncertain significance Arrhythmia 2016-03-15 criteria provided, single submitter clinical testing
Color RCV000584760 SCV001344564 uncertain significance Arrhythmia 2019-11-08 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058842 SCV000090362 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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