Submissions for variant NM_000335.5(SCN5A):c.4996G>A (p.Val1666Ile)

dbSNP: rs199473293

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523560	SCV000617273	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	The V1667I variant of uncertain significance in the SCN5A gene has been reported previously in association with arrhythmia (Piippo et al., 2001; Maekawa et al., 2005; Kapplinger et al., 2010; Hekkala et al., 2010). Initially, Piippo et al. (2001) reported V1667I in a Finnish individual with LQTS. Although this variant was identified in 8 additional family members, who on average had significantly longer QT intervals than family members who did not harbor the variant, only two of these family members also had a diagnosis of prolonged QT interval (Piippo et al., 2001). Subsequently, Maekawa et al. (2005) identified the V1667I variant in an individual with ventricular tachycardia who harbored a second variant in SCN5A and Kapplinger et al. (2010) identified the V1667I variant in an individual with suspected Brugada syndrome. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1667I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species in the transmembrane helical domain of the S5 region of repeat IV. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V1667I variant lacks sufficient evidence, including observation in a significant number of affected individuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001842375	SCV001357586	likely pathogenic	Cardiac arrhythmia	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1667 of the SCN5A protein. This variant is also known as p.Val1666Ile in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in transmembrane and linker regions have been shown to be significantly overrepresented in individuals with Long QT syndrome and Brugada syndrome (PMID: 32893267). An in vitro functional study has shown that this variant causes an increased sodium channel density, depolarizing shift in the steady-state inactivation, and accelerated recovery from inactivation (PMID: 32437023). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID:11274952, 15840476, 20129283, 27566755), in an individual affected with ventricular tachycardia (PMID: 15996170), in an individual affected with Brugada syndrome (PMID: 19843921), in three related individuals with epinephrine-induced marked QT prolongation (PMID: 32437023), and in an individual affected with arrhythmia with family history of sudden cardiac death (communication with an external laboratory; ClinVar SCV000617273.1). It has been shown that this variant segregates with disease in three of the families (PMID: 11274952, 32437023, communication with an external laboratory; ClinVar SCV000617273.1). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523560	SCV001539097	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1667 of the SCN5A protein (p.Val1667Ile). This variant is present in population databases (rs199473293, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome and Brugada syndrome (PMID: 2437023, 11274952, 19843921, 30291343, 32437023). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67949). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32437023). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336216	SCV002640654	likely pathogenic	Cardiovascular phenotype	2023-05-30	criteria provided, single submitter	clinical testing	The p.V1667I variant (also known as c.4999G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4999. The valine at codon 1667 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in individuals with long QT syndrome (LQTS), including segregating with disease in two families (Piippo K et al. Am. J. Cardiol., 2001 Apr;87:909-11; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Hekkala AM et al. Europace, 2010 Sep;12:1296-301; Määttänen I et al. J Psychosom Res, 2011 Oct;71:245-9; Määttänen I et al. Stress Health, 2013 Apr;29:150-5; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. J Cardiovasc Electrophysiol, 2020 Aug;31:2107-2115). Additionally, in vitro analysis showed this alteration may impact protein function (Nakajima T et al. J Cardiovasc Electrophysiol, 2020 Aug;31:2107-2115). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV001842375	SCV004820442	uncertain significance	Cardiac arrhythmia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1667 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). An in vitro functional study has shown that this variant causes an increased sodium channel density, depolarizing shift in the steady-state inactivation, and accelerated recovery from inactivation (PMID: 32437023). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID:11274952, 15840476, 20129283, 27566755), in an individual affected with ventricular tachycardia (PMID: 15996170), in an individual affected with Brugada syndrome (PMID: 19843921), in three related individuals with epinephrine-induced marked QT prolongation (PMID: 32437023), and in several asymptomatic relatives from two families (PMID:11274952, 32437023). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058734	SCV000090254	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:11274952;PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Medical Research Institute, Tokyo Medical and Dental University	RCV000190217	SCV000222068	likely pathogenic	Long QT syndrome		no assertion criteria provided	research