ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1385A>C (p.Glu462Ala) (rs199473114)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724465 SCV000225446 uncertain significance not provided 2015-02-10 criteria provided, single submitter clinical testing
GeneDx RCV000724465 SCV000235370 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing The E462A variant in the SCN5A gene has been reported in one individual referred for LQTS genetic testing and was absent in greater than 2,600 control alleles (Kapplinger et al., 2009). Clinical and family history information for this patient was not available and samples were included in this study regardless of the index of suspicion or the pre-test probability of a clinical diagnosis (Kapplinger et al., 2009). The E462A variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the E462A 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. This substitution occurs at a position that is conserved among mammals. Furthermore, a missense variant in the same residue (E462K) has been reported in an individual with a clinical diagnosis of LQTS referred for LQTS genetic testing and absent in 1,658 control alleles (Tester et al. 2005). However, clinical and family history information was not available due to the blinded nature of this study (Tester et al., 2005). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Color RCV001185987 SCV001352307 uncertain significance Arrhythmia 2019-05-30 criteria provided, single submitter clinical testing
Invitae RCV001216991 SCV001388816 uncertain significance Brugada syndrome 2019-05-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 462 of the SCN5A protein (p.Glu462Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with long QT syndrome (PMID: 28412158). ClinVar contains an entry for this variant (Variation ID: 67661). This variant has been reported not to substantially affect SCN5A protein function (PMID: 28412158, 25904541). This variant disrupts the p.Glu462 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 19841300, 24721456), which suggests that this may be a clinically significant amino acid residue. 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058420 SCV000089940 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). 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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