ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3157G>A (p.Glu1053Lys) (rs137854617)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469648 SCV000545106 uncertain significance Brugada syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1053 of the SCN5A protein (p.Glu1053Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs137854617, ExAC 0.03%). This variant has been reported in individuals with Brugada syndrome (PMID: 11901046, 19716085, 15579534, 20129283, 23321620), long QT syndrome (PMID: 20403459, 19026623), and atrial fibrillation (PMID: 18378609). This variant has also been observed in an individual who suffered sudden cardiac death; however, she also carried a SCN5A deletion, while an unaffected family member was homozygous for this p.Glu1053Lys variant (PMID: 28391114). ClinVar contains an entry for this variant (Variation ID: 9400). 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. Experimental studies have shown conflicting results. While this variant was shown to impair ankyrin-G binding and did not localize properly in cardiomyocytes in one experimental study (PMID: 15579534), a second study showed that channel activation in cardiomyocytes was unaffected in cells with reducted ankyrin-G expression and that neither ankyrin-G binding nor improper localization affected the function of the channel (PMID: 18180363). The clinical significance of these findings is unclear. 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755695 SCV000883127 likely pathogenic Long QT syndrome 3 2018-11-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV001186659 SCV001353193 uncertain significance Arrhythmia 2020-07-30 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 1053 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown conflicting results. One study has shown that this variant impairs ankyrin-G binding and causes mislocalization of the channel protein in cardiomyocytes (PMID: 15579534). A different study has shown that this variant does not affect channel activation in cardiomyocytes (PMID: 18180363). This variant has been reported in multiple individuals affected with or suspected of having Brugada syndrome (PMID: 11901046, 15579534, 20129283, 23321620), in a few individuals affected with or suspected of having long QT syndrome (PMID: 19026623, 19716085, 20403459) and in an individual with atrial fibrillation (PMID: 18378609). This variant has been reported in one case with sudden cardiac death, who also carried a de novo deletion in the SCN5A promoter region. Additionally, there were two heterozygous and one homozygous carriers of this variant without pathological phenotype in the family (PMID: 28391114). This variant has also been identified in 28/280210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, while this variant has been observed in multiple individuals affected with SCN5A-related disorders, it has also been observed in the general population and the variant impact on the protein function is not clear. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM RCV000010002 SCV000030223 pathogenic Brugada syndrome 1 2008-04-15 no assertion criteria provided literature only
OMIM RCV000022945 SCV000044236 pathogenic Atrial fibrillation, familial, 10 2008-04-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058552 SCV000090072 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528558 SCV001740461 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV001528558 SCV001921616 pathogenic not provided no assertion criteria provided clinical testing

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