ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5299A>G (p.Ile1767Val) (rs199473311)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620629 SCV000737391 pathogenic Cardiovascular phenotype 2016-06-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058766 SCV000090286 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:12209021;PMID:12566525;PMID:17905336;PMID:19841300;PMID:22370996;PMID:22373669). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics, Inc RCV000660252 SCV000782270 pathogenic Long QT syndrome 3 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000183198 SCV000235616 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing The I1768V pathogenic variant in the SCN5A gene has been reported previously in multiple unrelated individuals with a diagnosis of LQTS (Rivolta et al., 2002; Van Langen et al., 2003; Groenewegen et al. 2003; Hofman et al., 2010; Kauferstein et al., 2013). This variant was also shown to co-segregate with LQTS or significant bradycardia in six individuals from one family (Groenewegen et al., 2003). Functional studies have shown that the I1768V variant results in an increased rate of recovery from the inactive channel state and subsequent channel reopening allowing persistent inward current (Rivolta et al., 2002; Groenewegen et al., 2003; Kauferstein et al., 2013). I1768V is located in the transmembrane domain and missense variants in nearby residues (Y1767C, L1772V, N1774D, N1774S) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Furthermore, the I1768V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000537403 SCV000637178 pathogenic Brugada syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1768 of the SCN5A protein (p.Ile1768Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (rs199473311, ExAC no frequency). This variant has been reported in individuals and families affected with long QT syndrome (PMID: 12566525, 17088455, 17905336, 19841300, 21350584, 22373669). ClinVar contains an entry for this variant (Variation ID: 67980). This variant identified in the SCN5A gene is located in the transmembrane DIV-S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental studies have shown that this missense change increases the rate of channel recovery from activation and decreases the speed of inactivation (PMID: 12209021, 12650885). For these reasons, this variant has been classified as Pathogenic.

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