ClinVar Genomic variation as it relates to human health

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server). In addition, the variant has been reported previously in individuals with longQT syndrome. The variant results in an inframe deletion of one amino acid and thus reduces the length of the protein. Functional studies demonstrated that this variant alters sodium current kinetics (PMID: 14523039; PMID: 15665061).

Reported in multiple individuals in association with LQTS, Brugada syndrome, and sick sinus syndrome (SSS) (Splawski et al., 2000; Benson et al., 2003; Liang et al., 2006; Kapplinger et al., 2009, Zellerhoff et al., 2009; Liang et al., 2010; Crotti et al., 2012; Tan et al., 2014; Itoh et al., 2016; Fukuyama et al., 2020); Identified in 45 individuals from a large Dutch-German founder population, including one homozygous individual, and found that this variant segregated with divergent and overlapping cardiac phenotypes including LQTS, cardiac conduction disease (CCD), BrS, and isorhythmic dissociation (Ter Bekke et al., 2017); Published functional studies demonstrated that this variant alters sodium current kinetics and may cause both gain-of-function and loss-of-function effects on sodium currents, depending on the membrane potential (Benson et al., 2003; Chen et al., 2005; Gui et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14523039, 20539757, 15665061, 17081365, 19017345, 20877689, 22840528, 25236808, 26669661, 20448214, 28782696, 19716085, 24578642, 29017927, 30364184, 31582838, 32454217, 31737537, 32780330, 34426522, 33221895, 10973849, 32161207, 33673806)

This variant (rs749697698) is rare in a large population database (5/250930 total alleles, 0.002%, no homozygotes) and has an entry in ClinVar. This variant has been reported in families and/or individuals with autosomal dominant long QT syndrome-3 or Brugada syndrome-1. This variant causes a deletion of a single phenylalanine residue in the SCNA5 protein, which is located in the short extracellular loop between segments S3 and S4 in the repeat domain IV. Functional studies using cultured mammalian cells have demonstrated that this variant alters sodium current kinetics and may cause either an increase or decrease in sodium currents, depending on the membrane potential. We consider this variant to be pathogenic.

PS3, PP1_Strong PM4

Variant summary: SCN5A c.4850_4852delTCT (p.Phe1617del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 255580 control chromosomes (gnomAD). c.4850_4852delTCT has been reported in the literature in multiple individuals affected LQTS (examples: Splawski_2000, Kapplinger_2009, Goldenberg_2011), Sick Sinus syndrome (example: Benson_2003) and Brugada syndrome (examples: Liang_2010 and Crotti_2012). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies demonstrated that this variant alters sodium current kinetics and may cause either an increase or decrease in sodium currents (examples: Benson_2003, Chen_2005, Butters_2010 and Gui_2010). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant causes a deletion of phenylalanine at codon 1617 of the SCN5A protein. This variant is also known as Phe1616del 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 this region (a.a. 1530-1771) have been shown to be significantly overrepresented in individuals with long QT syndrome or Brugada syndrome (PMID: 32893267). Functional studies have shown that this variant causes a reduced peak sodium current density and also an increased sodium current at positive command potentials (PMID: 14523039, 15665061, 20448214). This variant has been reported in 45 individuals of the Netherlands and Germany descents in a 16-generation pedigree and has been shown to highly associate and segregate with long QT syndrome (PMID: 28782696). Some carriers in this founder population also exhibited other overlapping cardiac phenotypes including cardiac conduction defect, Brugada syndrome and/or isorhythmic atrioventricular dissociation. This variant has been observed in another two unrelated individuals affected with long QT syndrome (PMID: 10973849, 32454217), one individual affected with congenital sick sinus syndrome (PMID: 14523039), one with sudden explained death (PMID: 34620408), and several individuals with or suspected with Brugada syndrome (PMID: 20877689, 22840528, 32893267, 33221895, 36516610). This variant has been identified in 5/250930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The c.4850_4852delTCT variant (also known as p.F1617del) is located in coding exon 27 of the SCN5A gene. This variant results from an in-frame TCT deletion at nucleotide positions 4850 to 4852. This results in the in-frame deletion of a phenylalanine residue at codon 1617, located in the extracellular loop that links the S3 and S4 transmembrane-spanning helices of the DIV domain. This variant has been detected in individuals reported to have, or referred for genetic testing for, long QT syndrome (LQTS) and Brugada syndrome (BrS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Liang P et al. J Cardiovasc Dis Res. 2010;1(2):69-74; Crotti L et al. J Am Coll Cardiol. 2012;60(15):1410-8). This variant has also been reported to co-occur with other variants in arrhythmia-related genes, including a case of pediatric onset sick sinus syndrome, and severe LQTS where relatives with only this alteration were unaffected or less severely affected (Benson DW et al. J Clin Invest. 2003;112(7):1019-28; Tan VH et al. Heart Lung. 2014;43(6):541-5). One study of a Dutch-German population reported this alteration as a founder mutation that was significantly associated with the risk of long QT syndrome (Ter Bekke RMA et al. Heart Rhythm. 2017 12;14(12):1873-1881). Functional studies have suggested this variant alters sodium channel kinetics; however, the physiological relevance of the observed impact is unclear (Benson DW et al. J Clin Invest. 2003;112(7):1019-28; Chen T et al. Am J Physiol Heart Circ Physiol. 2005;288(6):H2666-76; Gui J. PLoS ONE. 2010;5(6):e10985). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 201572; PMID: 28782696; 25236808) - PS4. The variant is present at low allele frequencies population databases (rs749697698 - gnomAD 0.0001993%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant co-segregated with disease in multiple affected family members (PMID: 28782696; 25236808) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Criteria applied: PS4,PS3_MOD,PM4,PM2_SUP

This variant, c.4850_4852del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Phe1617del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749697698, gnomAD 0.003%). This variant has been observed in individuals with German-Dutch descent and long QT syndrome and sick sinus syndrome and long-QT syndrome and conduction disease and Brugada syndrome (PMID: 10973849, 14523039, 17081365, 19716085, 22840528, 28782696). It is commonly reported in individuals of Dutch ancestry (PMID: 10973849, 14523039, 17081365, 19716085, 22840528, 28782696). ClinVar contains an entry for this variant (Variation ID: 201572). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 15665061, 20448214). For these reasons, this variant has been classified as Pathogenic.