Submissions for variant NM_000335.5(SCN5A):c.5299A>G (p.Ile1767Val)

gnomAD frequency: 0.00001  dbSNP: rs199473311

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183198	SCV000235616	pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this 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); Reported in ClinVar as pathogenic (ClinVar Variant ID# 67980; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22581653, 12695286, 18929244, 12650885, 22370996, 12566525, 17905336, 17088455, 25804018, 31737537, 17556201, 12209021, 20513597, 22373669, 19841300)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183198	SCV000637178	pathogenic	not provided	2021-04-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). 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. 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 is not present in population databases (rs199473311, ExAC no frequency). 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.
Ambry Genetics	RCV000620629	SCV000737391	pathogenic	Cardiovascular phenotype	2016-06-08	criteria provided, single submitter	clinical testing	The p.I1768V pathogenic mutation (also known as c.5302A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 5302. The isoleucine at codon 1768 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a number of individuals diagnosed with long QT Syndrome (LQTS), and was shown to segregate with disease in one family (Rivolta I et al, Physiol. Genomics 2002 Sep; 10(3):191-7; Groenewegen WA et al, Cardiovasc. Res. 2003 Mar; 57(4):1072-8; Chung SK et al, Heart Rhythm 2007 Oct; 4(10):1306-14; Nannenberg EA et al, Circ Cardiovasc Genet 2012 Apr; 5(2):183-9; Kauferstein S et al, Int. J. Legal Med. 2013 Jan; 127(1):145-51). In addition, functional studies revealed that this alteration leads to altered recovery time from channel inactivation state (Rivolta I et al, Physiol. Genomics 2002 Sep; 10(3):191-7; Clancy CE et al, Circulation 2003 May; 107(17):2233-7; Groenewegen WA et al, Cardiovasc. Res. 2003 Mar; 57(4):1072-8; Kauferstein S et al, Int. J. Legal Med. 2013 Jan; 127(1):145-51). Based on the available evidence, p.I1768V is classified as a pathogenic mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660252	SCV000782270	pathogenic	Long QT syndrome 3	2016-11-01	criteria provided, single submitter	clinical testing
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.